TWI630206B - AMINO-SUBSTITUTED IMIDAZO[1,2-a]PYRIDINECARBOXAMIDES AND THEIR USE - Google Patents

Abstract

The present application relates to novel substituted imidazo [1,2-a] pyridine-3-carboxamides, a method for preparing the same, its use alone or in combination for treating and / or preventing diseases, and its use for preparing Pharmaceuticals are used for the treatment and / or prevention of diseases, especially for the treatment and / or prevention of cardiovascular disorders.

Description

Amine-substituted imidazo [1,2-a] pyridinecarboxamides and uses thereof

The present application relates to novel substituted imidazo [1,2-a] pyridine-3-carboxamides, a method for preparing the same, its use alone or in combination for treating and / or preventing diseases, and its use for preparing Pharmaceuticals are used for the treatment and / or prevention of diseases, especially for the treatment and / or prevention of cardiovascular disorders.

One of the most important cellular transport systems in mammalian cells is cyclic guanosine monophosphate (cGMP). It is together with the carbon monoxide (NO) released and transmitted by the endothelium and mechanical signals to form a NO / cGMP system. Guanylate cyclase catalyzes cGMP biosynthesis from guanosine triphosphate (GTP). The presently disclosed representatives of this family can be divided into two groups based on their structural characteristics and their types of ligands: granular guanylate cyclases that can be stimulated by natriuretic peptides, and those that can be stimulated by NO Soluble guanylate cyclase. The soluble guanylate cyclase system consists of two subunits and each heterodimer is likely to contain a heme, which is part of the regulatory site. The latter is very important for the activation mechanism. NO binds to the iron atom of heme and therefore significantly increases the activity of the enzyme. Heme-free preparations, by contrast, cannot be stimulated by NO. Carbon monoxide (CO) can also be linked to the iron atom in the center of heme, but it is obviously less stimulated by CO than NO.

Through the production of cGMP and the regulation of phosphodiesterase, iron channels and protein kinases, guanylate cyclase plays a key part in various physiological processes, especially smoothing Relaxation and proliferation of muscle cells, platelet aggregation and adhesion and neuronal signal transmission, and conditions caused by the aforementioned process damage. Under pathophysiological conditions, the NO / cGMP system may be inhibited, which may lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual disfunction.

A possible method for treating these conditions, which has nothing to do with NO and aims to affect the cGMP signal transmission path in the organism, is a promising method because of its high utility and few expected side effects.

Compounds, such as organic nitrates, are based on NO and are currently used alone for the therapeutic stimulation of soluble guanylate cyclases. NO is produced by biotransformation and activates soluble guanylate cyclase by iron binding to the center of heme. In addition to side effects, tolerability is one of the important disadvantages of this treatment model.

In the past few years, many substances that directly stimulate soluble guanylate cyclase, that is, do not release NO first, have been described, such as 3- (5'-hydroxy-methyl-2'-furanyl)- 1-benzylindazole [YC-1; Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J. Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J Biol. Chem. 252 (1977), 1279], biphenyl iodonium hexafluorophosphate [Pettibone et al., Eur. J. Pharmacol. 116 (1985), 307], isoliquiritigenin [Yu et al. , Brit. J. Pharmacol. 114 (1995), 1587] and various substituted pyrazole derivatives (WO 98/16223).

EP 0 266 890-A1, WO 89 / 03833-A1, JP 01258674-A [see Chem. Abstr. 112: 178986], WO 96 / 34866-A1, EP 1 277 754-A1, WO 2006 / 015737-A1 WO 2008 / 008539-A2, WO 2008 / 082490-A2, WO 2008 / 134553-A1, WO 2010 / 030538-A2, WO 2011 / 113606-A1 and WO 2012/165399 A, among others, describe a variety of useful methods for treating disorders Imidazole [1,2-a] pyridine derivative.

An object of the present invention is to provide a stimulant for soluble guanylate cyclase, And, for example, novel substances suitable for treating and / or preventing diseases.

The present invention provides compounds of general formula (I) Wherein A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be independently replaced by fluorine, trifluoromethyl and (C ₁ -C ₄ )-Alkyl group selected by substituents, and phenyl groups can be independently selected from halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C _1- C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, difluoromethoxy and trifluoromethoxy groups selected from the group consisting of substituents, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, R ³ represents a group of the formula * represents a point of attachment to a carbonyl group L ^1A Represents a bond or (C ₁ -C ₄ ) -alkylene, in which (C ₁ -C ₄ ) -alkylene can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C _3-

Wherein C ₇ ) -cycloalkyl, hydroxy and (C ₁ -C ₄ ) -alkoxy groups are substituted by selected substituents, L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, in which (C ₁ -C ₄ ) -alkylene can be independently selected from fluorine, trifluoromethyl, ( C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy group selected from the group consisting of substituents, R ⁷ represents hydrogen (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, 5- or 6 -Membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoro via 1 to 3 Methoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxy-carbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, phenyl, benzene Selected from the group consisting of oxy and benzyloxy, in which phenyl, phenoxy and benzyloxy may themselves be substituted with 1 to 3 halogen substituents, of which (C ₃ -C ₇ ) -cycloalkane 1 to 2 groups may independently of one another by fluorine, trifluoromethyl, (C ₁ -C ₄₎ - alkyl (C ₁ -C ₄₎ - alkoxy group composed of the selected substituents, and wherein phenyl and 5- or 6-membered heteroaryl with 1 to 3 may be independently of one another by halogen, cyano, Selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkylsulfonyl and (C ₁ -C ₄ ) -alkoxy , R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl, or R ⁷ and R ⁸ together form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocycle Ring, wherein the 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring itself may be selected from 1 to 2 groups independently of each other consisting of fluorine and (C ₁ -C ₄ ) -alkyl Substituent substitution, R ⁹ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -Cycloalkyl, 5- or 6-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy through 1 to 3 Group, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, benzene Selected from the group consisting of phenyl, phenoxy and benzyloxy, wherein phenyl, phenoxy Itself and benzyloxy may be substituted with 1 to 3 halogen substituents, wherein (C _3, and -C ₇₎ - cycloalkyl may be independently 1-2 by fluoro, trifluoromethyl, (C ₁ - C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy group selected substituents, and the phenyl group and 5- or 6-membered heteroaryl group can be independent from each other by 1 to 3 Is composed of halogen, cyano, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, and (C ₁ -C ₄ ) -alkylsulfonyl Substituted by a substituent selected from the group, R ¹⁰ represents hydrogen or (C ₁ -C ₄ ) -alkyl, or R ⁹ and R ¹⁰ form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring and 4- to 7-membered heterocyclic ring itself may be independently substituted by fluorine and (C ₁ -C ₄ ) -alkane through 1 to 2 The substituents selected from the group consisting of substituents are subject to the limitation that both R ⁷ and R ⁹ groups cannot represent a phenyl group at the same time, or that R ⁷ and R ⁹ are connected to the carbon atom and the L ^1B group to form a 5- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring, the restriction is that each of R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot have more than one pair Simultaneously Into carbon - or heterocycle, R ¹¹ represents hydrogen or lines (C ₁ -C ₄₎ - alkyl, wherein the (C ₁ -C ₄₎ - alkyl group with 1 to 3 can be independently of one another by fluorine, trifluoromethanesulfonate Selected from the group consisting of alkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ )- Cycloalkyl, phenyl or benzyl, where (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy via 1 to 3 And a phenoxy group, and the phenyl and benzyl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen and trifluoromethyl, or R ¹¹ and R ¹² together form a 4- to 7-membered nitrogen heterocyclic ring with the nitrogen atom to which they are connected, wherein the 4- to 7-membered nitrogen heterocyclic ring can be independently replaced by fluorine or trifluoromethyl via 1 or 2 Group consisting of: (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, and 4- to 7-membered heterocyclic ring And selected substituents, and L ² represents a bond or (C ₁ -C ₄ ) -alkylene, and R ¹³ represents a 5- to 9-membered nitrogen heterocyclic ring connected through a ring carbon atom, of which 5 -To 9- Member nitrogen heterocycles may be in groups of 1 to 5 independently consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and benzyl Selected substituent substitution, and 5- to 9-membered nitrogen heterocycles may be fused with phenyl, and the phenyl itself may be substituted by 1 or 2 by halogen, (C ₁ -C ₄ ) -alkyl and trifluoro R ⁴ represents hydrogen, R ⁵ represents hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₂ -C ₄ ) -alkynyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, 4- to 7-membered heterocycle or 5- or 6-membered heteroaryl, R ⁶ represents hydrogen, cyano or halogen, and its N-oxides, salts, solvates, N-oxide salts and N- Solvents of oxides and salts.

The present invention provides compounds of general formula (I) Where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be independently replaced by fluorine, trifluoromethyl and (C ₁ -C ₄ )-Alkyl group selected by substituents, and phenyl groups can be independently selected from halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C _1- C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, difluoromethoxy and trifluoromethoxy groups selected from the group consisting of substituents, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, R ³ represents a group of the formula Or

Where * represents the point of attachment to the carbonyl group, and L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene may be bonded to each other via 1 to 3 Independently consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, and (C ₁ -C ₄ ) -alkoxy Selected substituents are substituted, L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C _1- C ₄ ) -alkoxy group selected substituents, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, cyano, 5- to 10-membered heteroaryl, naphthyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl Can be independently from 1 to 3 by fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄₎ - alkoxycarbonyl, (C ₁ -C ₄₎ - alkylsulfonyl, phenyl, phenoxy and benzyloxy groups Selected from the group of substituents, wherein phenyl, phenoxy and benzyloxy may be itself or 3 halogen (C ₁ -C ₄₎ with 1 to - substituted alkoxy substituent, wherein (C ₃ -C ₇ ) -Cycloalkyl can be selected from 1 or 2 groups independently consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy Substituted by substituents, and phenyl and 5- to 10-membered heteroaryl groups thereof may be independently substituted by 1 to 3 halogen, cyano, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy Group, trifluoromethoxy, -NH (CO) CH ₃ , (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkyl, (C ₁ -C ₄ ) -alkenyl, (C ₁ -C ₄ ) -alkylsulfonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxy groups selected from the group consisting of (where C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, and two adjacent carbon atoms of the phenyl group may be substituted by a difluoromethylenedioxy bridge, R ⁸ represents hydrogen or (C _1- C ₄ ) -alkyl, or R ⁷ and R ⁸ together form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring together with the carbon atom to which they are attached, wherein the 3- to 7-membered carbon Rings and 4- to 7-membered heterocycles can themselves pass through 1 or 2 phases Independently substituted by a substituent selected from the group consisting of fluorine and (C ₁ -C ₄ ) -alkyl, R ⁹ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -Alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, 5- to 10-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkane The radical may be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ Selected from the group consisting of) -alkoxy-carbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, 5- or 6-membered heteroaryl, phenyl, phenoxy, and benzyloxy Substitution, in which phenyl, phenoxy, and benzyloxy may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, wherein 5- or 6-membered heteroaryl may be benzene Fused-fused or substituted with 5- or 6-membered heteroaryl, wherein 5- or 6-membered heteroaryl may be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C ₃ -C ₇ ) -Cycloalkyl can be independently composed of 1 or 2 groups consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy The selected substituents may be substituted, and the phenyl group and the 5- to 10-membered heteroaryl group may be separated from each other by 1 to 3 By halogen, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄₎ - alkyl, (C ₁ -C ₄₎ - cycloalkyl Selected from the group consisting of (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl, Wherein (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, and the phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms, and R ¹⁰ represents hydrogen or (C _1- C ₄ ) -alkyl, or R ⁹ and R ¹⁰ together form a 3- to 7-membered carbocyclic or 4- to 7-membered heterocyclic ring with the carbon atom to which they are attached, wherein the 3- to 7- The member carbocyclic ring and the 4- to 7-membered heterocyclic ring itself may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and (C ₁ -C ₄ ) -alkyl independently of each other. Provided that both R ⁷ and R ⁹ groups cannot represent phenyl groups at the same time, or that R ⁷ and R ⁹ are connected to the carbon atom and L ^1B group to form a 3- to 7-membered carbocyclic ring or 4- to 7 -Membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring may be independently from each other by (C ₁ -C ₄ ) -alkyl, fluorine, hydroxyl and (C ₁ -C ₄ ) -alkoxy Selected substitutions Substituents, with the proviso that respective R ⁷ and R ^8, R ⁹ and R ¹⁰ and R ⁷ and R ⁹ can not have a group of one or more pairs of carbon formed simultaneously - or heterocycle, R ¹¹ represents hydrogen or line (C _1- C ₄ ) -alkyl, wherein (C ₁ -C ₄ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy via 1 to 3 Selected from the group consisting of substituents, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, where (C _1- C ₆ ) -alkyl may be substituted with 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, And its phenyl and benzyl groups may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen and trifluoromethyl, or R ¹¹ and R ¹² together form a nitrogen atom with 4 -To 7-membered nitrogen heterocyclic ring, wherein the 4- to 7-membered nitrogen heterocyclic ring may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and 4- to 7-membered heterocyclic ring selected from the group consisting of substituents, and L ² represents A bond or (C ₁ -C ₄ ) -alkylene, R ¹³ represents a 5- to 9-membered nitrogen heterocycle, which is linked via a ring carbon atom, where the 5- to 9-membered nitrogen heterocycle may be 1 to 5 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, and benzyl, Among them, the 5- to 9-membered nitrogen heterocyclic ring can be condensed with the phenyl ring, and the phenyl ring itself can pass 1 or 2 halogens, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ )- A substituent selected from the group consisting of alkoxy and trifluoromethyl, or represents adamantyl, R ⁴ represents hydrogen, and R ⁵ represents hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl Group, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₂ -C ₄ ) -alkynyl, difluoromethoxy, trifluoromethyl Oxygen, (C ₁ -C ₄ ) -alkoxy, amine, 4- to 7-membered heterocyclic or 5- or 6-membered heteroaryl, R ⁶ represents hydrogen, cyano or halogen, and N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

The compounds of the present invention are compounds of formula (I) and their salts, solvates and solvates of salts, and compounds of formula (I) and their salts, solvates and salts of solvents contained in the following formulae Compounds, and the compounds mentioned in formula (I) and the following as specific examples, and the salts, solvates and solvates of the salts thereof, the compounds contained in the formula (I) and the following are not yet For salts, solvates and solvates of salts.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the present invention. It also covers salts which are not suitable for pharmaceutical applications per se, but can be used, for example, to isolate and purify the compounds of the invention.

The physiologically acceptable salts of the compounds of the present invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid Acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid salts.

The physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases, such as, for example, and preferably alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), and Derived from ammonia or organic amines with ammonium salts having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylaminoethanol, procain, dibenzylamine, N- Methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

The solvate in the context of the present invention designates the form of the compound of the present invention which forms a solid or liquid complex by coordination with a solvent molecule. A hydrate is a specific form of a solvate in which it is coordinated with water. In the context of the present invention, hydrates are preferred solvates.

According to its structure, the compounds of the present invention may exist in different stereoisomeric forms, that is, configurational isomers or conformational isomers (mirror isomers and / or diastereomers, including the In the case of atropisomers). The present invention therefore includes mirror and isomers and specific mixtures thereof. Stereoisomerically homogeneous constituents can be separated from such mixtures of mirror isomers and / or diastereomers by known methods; for this purpose, it is preferred to be in the opposite palm or opposite palm phase Chromatography is used, and more specifically, HPLC chromatography.

Where the compounds of the invention can occur in tautomeric forms, the invention includes all tautomeric forms.

The invention also encompasses all suitable isotopic variations of the compounds of the invention. Please understand that an isotope variant of a compound of the present invention refers herein to a compound in which at least one atom in the compound of the present invention is exchanged with another atom having the same atomic number but an atomic weight different from that normally or mainly occurring in nature. Examples of isotopes that can be incorporated into the compounds of the present invention are such isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C , ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I, and ¹³¹ I. Special isotopic variants of the compounds of the invention, such as, in particular, those that incorporate one or more radioisotopes, may be useful, for example, for testing of mechanisms of action or distribution of drugs in the body; Easy, compounds calibrated with ³ H or ¹⁴ C isotopes are particularly suitable for this purpose. In addition, the incorporation of isotopes, such as deuterium, may cause certain therapeutic benefits due to the compound's better metabolic stability, such as extending the half-life in the body or reducing the effective dose required; these modifications of the compounds of the invention Therefore, it also constitutes a preferred embodiment of the present invention in some cases. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, such as the methods described below and the methods described in the operating examples, by using the corresponding reagents and / or starting compounds. Isotope modification.

Furthermore, the present invention also includes prodrugs of the compounds of the present invention. As used herein, the term "prodrug" refers to a compound that is biologically activated or non-activated, but which is transformed (eg, metabolized or hydrolyzed) into a compound of the invention while it is in the body.

In the context of the present invention, unless otherwise stated, the substituents have the following meanings: In the context of the present invention, an alkyl group represents a straight or branched chain alkyl group having a specific number of carbon atoms in each case. Mention may be made as examples and preferably the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, third butyl, n-pentyl, Isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3 -Methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl.

A cycloalkyl or carbocyclic ring in the context of the present invention represents a monocyclic saturated alkyl group having the number of carbon atoms referred to in each case. Mention may be made as examples and preferably the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkenyl in the context of the present invention represents a straight or branched chain alkenyl group having 2 to 6 carbon atoms and one or two double bonds. A preferred system is a straight or branched chain alkenyl group having 2 to 4 carbon atoms and a double bond. Mention may be made as examples and preferably the following: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

Alkynyl in the context of the present invention represents a straight or branched chain alkynyl group having 2 to 6 carbon atoms and a triple bond. Mention may be made as examples and preferably the following: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl, and n-but- 3-alkyn-1-yl.

Alkylene in the context of the present invention represents a straight or branched chain divalent alkyl group having from 1 to 4 carbon atoms. Mention may be made as examples and preferably the following: methyl, 1,2-ethyl, ethyl Alkane-1,1-diyl, 1,3-propane, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, 1,4-butane Base, butane-1,2-diyl, butane-1,3-diyl, and butane-2,3-diyl.

Alkoxy in the context of the present invention represents a straight or branched chain alkoxy group having 1 to 4 carbon atoms. Mention may be made as examples and preferably the following: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tertiary Butoxy.

Alkoxycarbonyl in the context of the present invention represents a straight or branched chain alkoxy group having from 1 to 4 carbon atoms and a carbonyl group attached to an oxygen atom. Mention may be made as examples and preferably the following: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Alkylsulfonyl refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms and linked via a sulfonyl group in the context of the present invention. Mention may be made as examples and preferably the following: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl醯 基.

4- to 7-membered heterocyclic rings represent monocyclic saturated heterocyclic rings having a total of 4 to 7 ring atoms in the context of the present invention, which contain one or two consisting of N, O, S, SO and / or SO ₂ The selected ring heteroatom in the group is connected via a ring carbon atom or a ring nitrogen atom if necessary. Mention may be made as examples of the following: aziridinyl, oxenyl, pyrrolidinyl, pyrazolidyl, tetrahydrofuranyl, thiol Base, piperidinyl, piperidine Radical, tetrahydropiperanyl, tetrahydrothiapiperanyl, morpholinyl, timorpholinyl, hexahydroazepine and hexahydro-1,4-diazepine. It is preferably administered with aziridinyl, oxenyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperidine , Tetrahydropiperanyl and morpholinyl.

4- to 7-membered nitrogen heterocycles represent monocyclic saturated heterocycles with a total of 4 to 7 ring atoms in the context of the present invention, which contain one nitrogen atom and which may additionally contain N, O, S, SO And / or other ring heteroatoms selected from the group consisting of SO ₂ are connected via a ring nitrogen atom. Mention may be made as examples of the following: azepine, pyrrolidinyl, pyrazolidyl, piperidinyl, piperidinyl Group, morpholinyl, timorpholinyl, 1,1-dioxothiamorpholinyl, hexahydroazepine and hexahydro-1,4-diazepine.

5- to 9-membered nitrogen heterocyclyl represents monocyclic or bicyclic saturated or partially saturated heterocyclic rings having a total of 5 to 9 ring atoms in the context of the present invention, which contains one nitrogen atom and which may additionally contain one or Two other ring heteroatoms selected from the group consisting of N, O, S, SO and / or SO ₂ are connected via a ring carbon atom. The following may be mentioned as examples: pyrrolidinyl, pyrazoridinyl, piperidinyl, piperidinyl Group, morpholinyl, timorpholinyl, 1,1-dioxothiamorpholinyl, hexahydroazepine and hexahydro-1,4-diazepine, 1,2,3,4 -Tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3. 1] nonyl, 3-azabicyclo [4.1.0] heptyl and Pyridyl.

Heteroaryl in the context of the present invention represents a monocyclic or optionally bicyclic aromatic heterocyclic group (heteroaromatic) having a total of 5 to 10 ring atoms, each containing up to three components from N, O and / or S The groups of the same or different ring heteroatoms are connected via a ring carbon atom or, if necessary, a ring nitrogen atom. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, Oxazolyl, iso Oxazolyl, isothiazolyl, triazolyl, Oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, Base Base, three Base, benzofuranyl, benzothienyl, benzimidazolyl, benzo Oxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolyl, naphthyridyl, quinazolinyl, quinazolinyl, pyrene , Pyrazolo [3,4-b] pyridyl. Heteroaryl groups in the context of the present invention preferably represent aromatic heterocyclic groups (heteroaromatics) having a total of 5 or 6 ring atoms, respectively, which contain up to three groups of the same or The different ring heteroatoms are connected via a ring carbon atom or, if desired, a ring nitrogen atom. May be mentioned as examples and preferably the following: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, Oxazolyl, iso Oxazolyl, isothiazolyl, triazolyl, Oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, Base Base and three base.

Halogen in the context of the present invention includes fluorine, chlorine, bromine and iodine. Preferably, chlorine or fluorine is administered.

In the chemical formula that can represent a group of R ³ or R ^1, the endpoints of the straight lines marked with * or # marks do not represent carbon atoms or CH ₂ groups, but form part of the bond and in each case It refers to an atom or bonded to each of R ³ and R ¹ .

If the groups in the compounds of the present invention are substituted, these groups are mono- or poly-substituted unless otherwise stated. In the context of the present invention, all groups that occur more than once are defined independently of one another. Substitution by one, two or three identical or different group substituents is preferred.

In the context of the present invention, the term "treatment" refers to inhibiting, delaying, preventing, ameliorating, attenuating, limiting, reducing, suppressing or curing conditions, symptoms, disorders, injuries and health damage, such symptoms and / Or the occurrence, process, or course of symptoms of these symptoms. The term "therapy" is understood herein to be the same as "treatment".

In the context of the present invention, the terms "prevention", "prophylaxis", and "preclusion" are synonymous in use and refer to avoiding or reducing access, experience, experience, or having a disease or disorder Risk of occurrence, process or course of severe, illness, injury or health impairment, these symptoms and / or symptoms of these symptoms.

Treatment or prevention of a disease, severity, condition, injury, or health impairment may be partial or complete.

In the context of the present invention, it is preferred to administer a compound of formula (I), wherein A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, ( C ₄ -C ₆₎ - cycloalkyl, or phenyl, wherein (C ₄ -C ₆₎ - alkyl which may be substituted by fluorine High 6, wherein (C ₄ -C ₆₎ - cycloalkyl may be substituted with 1 or 2 Each independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and methyl, and its phenyl group may be independently substituted by fluorine, chlorine, cyano, methoxy, di Selected from the group consisting of fluoromethyl, trifluoromethyl and methyl, R ² represents hydrogen, trifluoromethyl, (C ₁ -C ₄ ) -alkyl or cyclopropyl, R ³ is Represents a group of the formula Or

Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, methyl or 1,2-ethylene, and L ^1C represents a bond or methyl, where The methyl group may be substituted by 1 or 2 substituents selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ represents hydrogen , Trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, where (C ₁ -C ₆ ) -Alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl, benzene via 1 or 2 Selected from the group consisting of oxy and benzyloxy, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with 1 or 2 substituents selected from the group consisting of fluorine and chlorine, where ( C ₃ -C ₆ ) -cycloalkyl may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and phenyl and 5- or 6-membered heteroaryl can be independently composed of 1 or 2 of fluorine, chlorine, cyano, methyl and trifluoromethyl Substituents selected from the substituent group, the carbon-based R ⁸ represents hydrogen atom, methyl or ethyl, or R ⁷ and R ⁸ lines connected thereto together form a 3- to 6-membered carbocyclic or oxygen Ta, tetrahydrofuranyl , Tetrahydropiperanyl, azetino, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxonyl, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidine Or a piperidinyl ring may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other, R ⁹ represents hydrogen, 1,1,2,2-tetrafluoroethyl, tris Fluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, of which (C ₁ -C ₆ ) -alkane The radical may be independently or independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl, and phenoxy groups. And benzyloxy selected from the group consisting of substituents, wherein phenyl, phenoxy and benzyloxy themselves can be substituted with 1 or 2 groups selected from the group consisting of fluorine and chlorine, where (C ₃ -C ₆ ) -Cycloalkyl may be independently composed of fluorine, trifluoromethyl, methyl and ethyl via 1 or 2 The selected substituents in the group are substituted, and the phenyl group and the 5- or 6-membered heteroaryl group may be substituted by 1 or 2 groups independently consisting of fluorine, chlorine, cyano, methyl and trifluoromethyl. Selected substituents are substituted. R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ are a carbon atom to which they are attached to form a 3- to 6-membered carbocyclic or an oxo, tetrahydrofuranyl group. , Tetrahydropiperanyl, azetino, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxonyl, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidin Or a piperidinyl ring may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other, with the limitation that both R ⁷ and R ⁹ groups cannot simultaneously represent phenyl, or R ⁷ and R ⁹ together form a cyclopentyl, cyclohexyl, aziridinyl, oxenyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropiperidinyl ring together with the carbon atom and L ^1B group to which they are attached, The limiting condition is that each of the R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ group pairs cannot form one of the above carbon- or heterocyclic ring at the same time, and R ¹¹ represents hydrogen or ( C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl can be selected from 1 or 2 groups independently of each other consisting of fluorine, trifluoromethyl, hydroxyl, methoxy and ethoxy R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, cyclobutyl, phenyl, or benzyl. (C ₁ -C ₄ ) -alkyl may be substituted by 1 Or two substituents independently selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and the phenyl and benzyl groups thereof may be substituted by 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine and trifluoromethyl, or R ¹¹ and R ¹² together form a nitrogen atom, pyrrolidyl, piperidine Pyridyl, morpholinyl, piperidine Group, timorpholinyl or 1,1-dioxotimorpholinyl ring, wherein aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl Can be independently selected from fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl via 1 or 2 Selected from the group consisting of N-, aziridinyl, pyrrolidinyl, and piperidinyl, and L ² represents a bond, methyl or 1,1-ethylene, and R ¹³ represents pyrrolidinyl , Piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1] Octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo- [4.1.0] heptyl, and those linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-aza Bicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen , R ⁵ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl or cyclopropyl, R ⁶ represents hydrogen or fluorine, and its N-oxides, salts, solvates, N-oxidation Salts of substances and solvates of N-oxides and salts.

In the context of the present invention, it is preferred to administer a compound of formula (I), where A represents CH ₂ , R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkane Or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, where (C ₄ -C ₆ ) -cycloalkyl can be independently replaced by fluorine or trifluoro through 1 or 2 Methyl and methyl groups are substituted with selected substituents, and phenyl groups thereof may be selected from 1 to 4 groups independently consisting of fluorine, chlorine, difluoromethyl, trifluoromethyl and methyl R ² represents a (C ₁ -C ₃ ) -alkyl, trifluoromethyl or cyclopropyl group, and R ³ represents a group of the formula Or

Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass through one or two methyl groups. Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents hydrogen, trifluoromethyl, (C _1- C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and trifluoromethyl via 1 or 2 Selected from the group consisting of phenyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, and benzyloxy, wherein phenyl, phenoxy, and benzyloxy may themselves be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine, trifluoromethyl, methyl and Substituents selected from the group consisting of ethyl groups, and phenyl groups thereof may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, and trifluoromethyl groups independently, R ⁸ is Represents hydrogen, methyl or ethyl, or the carbon to which R ⁷ and R ⁸ are bound The atoms together form a 3- to 6-membered carbocyclic or oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azetino, pyrrolidinyl, or piperidinyl ring, wherein the 3- to 6-membered carbocyclic and The oxo, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidinyl, or piperidinyl rings may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other, R ⁹ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, where (C ₁ -C ₆ ) -alkyl may be substituted by 1 Or two substituents independently selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, and benzyloxy, wherein benzene Group, phenoxy group and benzyloxy group may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl group may be independent of each other through 1 or 2 It is substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, and the phenyl group thereof may be independently composed of fluorine, chlorine, cyano and trifluoromethyl through 1 or 2 selected from the group of substituents, R ¹⁰ lines represents hydrogen, methyl or Carbon atom, or R ⁹ and R ¹⁰ lines connected thereto together form a 3- to 6-membered carbocyclic group or an oxygen Ta, tetrahydrofuranyl, tetrahydropyranyl group, a nitrogen group Ya, pyrrolidinyl or piperidinyl Radicals, wherein the 3- to 6-membered carbocyclic and oxo, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidinyl, or piperidinyl rings can be independently replaced by fluorine through 1 or 2 The substituents selected from the group consisting of methyl and methyl are subject to the limitation that the R ⁷ and R ⁹ groups cannot represent phenyl at the same time, or that R ⁷ and R ⁹ are a carbon atom and L ^1B group connected to form a cyclopentyl group. Group, cyclohexyl, aziridinyl, oxenyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropiperidinyl rings, and the restrictions are R ⁷ and R ⁸ , R ⁹ and R ^10, and There cannot be more than one pair of R ⁷ and R ⁹ groups forming one of the above carbon- or heterocyclic rings. R ¹¹ represents hydrogen or (C ₁ -C ₃ ) -alkyl, in which (C ₁ -C ₃ )- Alkyl groups may be substituted by 1 or 2 groups independently selected from the group consisting of fluorine and trifluoromethyl, R ¹² representing hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl or cyclobutyl substituents, wherein (C ₁ -C ₄₎ - alkyl can Or two groups independently of one another by fluorine and trifluoromethyl selected one of the substituents R ¹² or R ¹¹ and connecting the lines together with the nitrogen atom form a nitrogen-Ya-yl, pyrrolidinyl, piperidinyl Or a morpholinyl ring, wherein the aziridinyl, pyrrolidinyl, piperidinyl, and morpholinyl rings may be independently selected from fluorine, trifluoromethyl, methyl, ethyl, and Selected from the group consisting of propyl and cyclobutyl, and L ² represents a bond or a methyl group, and R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydro Isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] non , 3-azabicyclo [4.1.0] heptyl, and those linked via a ring carbon atom Pyridyl, or of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 8-azabicyclo [3.2 .1] octyl, 9-azabicyclo- [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen , R ⁵ represents hydrogen, fluorine, chlorine, methyl, ethyl or cyclopropyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, N-oxide salts and N- Solvents of oxides and salts.

In the context of the present invention, particularly preferred is the administration of a compound of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula

Where # is the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ are independently of each other hydrogen, fluorine or chlorine. The restriction is that at least two R ¹⁴ , R ¹⁵ and R ^{16 are} not hydrogen, ² represents methyl, R ³ represents a group of the formula Or

Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, ( C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and phenyl may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and chlorine, R ⁸ represents hydrogen, methyl or ethyl, R ⁹ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, cyclopropyl or phenyl, of which (C ₁ -C ₆ )- Alkyl groups may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenyl groups, and Substituted by 1 or 2 substituents independently selected from the group consisting of fluorine and chlorine, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ together form a carbon atom to which they are attached. 3- to 6-membered carbocyclic or oxo ring, the limitation is that R ⁷ and R ⁹ groups cannot be simultaneously Represents a phenyl group, or R ⁷ and R ⁹ are a carbon atom and a L ^1B group to which they are attached to form a cyclopentyl or cyclohexyl ring, and the restrictions are R ⁷ and R ⁸ , R ⁹ and R ^10, and There cannot be more than one pair of R ⁷ and R ⁹ groups forming one of the above carbon- or heterocyclic rings. R ¹¹ represents hydrogen, R ¹² represents hydrogen, and L ² represents a bond, and R ¹³ represents piperidine. 2-yl, piperidin-3-yl, piperidin-4-yl or 1,2,3,4-tetrahydroquinolin-4-yl, among which piperidin-2-yl, piperidin-3-yl And piperidin-4-yl may be substituted by 1 to 5 substituents selected independently from trifluoromethyl and methyl, and 1,2,3,4-tetrahydroquinolin-4-yl may be substituted by Fluorine or trifluoromethyl substitution, R ⁴ represents hydrogen, R ⁵ represents hydrogen, fluorine, chlorine or methyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, N-oxides Salts and solvates of N-oxides and salts.

In the context of the present invention, it is preferred to administer a compound of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), and R ¹ represents phenyl, wherein phenyl may be Independently substituted by a substituent selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, and the phenyl group is 1 or 2 substituents selected from the group consisting of (C ₃ -C ₆ ) -cycloalkyl, (C ₁ -C ₄ ) -alkoxy, difluoromethoxy and trifluoromethoxy, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl, and R ³ represents a group of the formula or

Where * represents the point of attachment to the carbonyl group L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene can be independent of each other via 1 to 3 Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, and L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene can be independently selected from fluorine, trifluoromethyl (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C _1- C ₄ )-Alkoxy group consisting of selected substituents, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, cyano, 5- or 10-membered heteroaryl, naphthyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl may be 1 to 3 each independently of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -mercapto , (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, phenyl, phenoxy and benzyloxy Selected substituents in the group, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, in which (C ₃ -C ₇ ) -Cycloalkyl can be selected from 1 or 2 groups independently consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy And its substituents, and its phenyl and 5- to 10-membered heteroaryl groups may be independently substituted by halogen, cyano, nitro, difluoromethyl, trifluoromethyl, difluoromethyl through 1 to 3 Oxy, trifluoromethoxy, -NH (CO) CH ₃ , (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkyl, (C ₁ -C ₄ ) -alkenyl , (C ₁ -C ₄ ) -alkylsulfonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxy group selected from the group consisting of substituents, wherein (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, and the phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms. R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl, or R ⁷ and R ⁸ together form a 3- to 7-membered carbocyclic or 4- to 7-membered heterocyclic ring with the carbon atom to which they are attached, wherein the 3- to 7-membered Carbocycles and 4- to 7-membered heterocycles can themselves pass through 1 or 2 Mutual fluorine and (C ₁ -C ₄₎ independently - selected from the group consisting of alkyl substituents, R ⁹ represents hydrogen system, (C ₁ -C ₆₎ - alkyl, (C ₂ -C ₆₎ -Alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, 5- to 10-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkane The radical may be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ Selected from the group consisting of) -alkoxy-carbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, 5- or 6-membered heteroaryl, phenyl, phenoxy, and benzyloxy Substitution, in which phenyl, phenoxy, and benzyloxy may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, wherein 5- or 6-membered heteroaryl may be benzene And fused or substituted with 5- or 6-membered heteroaryl, wherein 5- or 6-membered heteroaryl may be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C _3- C ₇ ) -Cycloalkyl groups may be independently composed of 1 or 2 groups consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy Selected substituents can be substituted, and the phenyl and 5- or 6-membered heteroaryl groups can be separated from each other by 1 to 3 By halogen, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄₎ - alkyl, (C ₁ -C ₄₎ - cycloalkyl Selected from the group consisting of (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl, Wherein (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, and the phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms, and R ¹⁰ represents hydrogen or (C _1- C ₄ ) -alkyl, or R ⁹ and R ¹⁰ together form a 3- to 7-membered carbocyclic or 4- to 7-membered heterocyclic ring with the carbon atom to which they are attached, wherein the 3- to 7- The member carbocyclic ring and the 4- to 7-membered heterocyclic ring itself may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and (C ₁ -C ₄ ) -alkyl independently of each other. Provided that the R ⁷ and R ⁹ groups cannot represent phenyl groups at the same time, or that R ⁷ and R ⁹ are linked to the carbon atom and L ^1B group to form a 3- to 7-membered carbocyclic ring or 4- to 7-membered Heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring may be independently composed of (C ₁ -C ₄ ) -alkyl, fluorine, hydroxyl, and (C ₁ -C ₄ ) -alkoxy via 1 or 2 Selected substituents , With the proviso that respective R ⁷ and R ^8, R ⁹ and R ¹⁰ and R ⁷ and R ⁹ can not have a group of more than one pair of the carbon formed simultaneously - one or heterocycle, R ¹¹ represents hydrogen or based (C ₁ -C ₄ ) -alkyl, wherein (C ₁ -C ₄ ) -alkyl may be independently selected from fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkane via 1 to 3 Substitutes selected from the group consisting of oxy groups, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, where (C _1- C ₆ ) -alkyl may be substituted through 1 to 3 substituents independently selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy Substitution, and the phenyl and benzyl groups thereof may be substituted by 1 to 3 substituents selected from the group consisting of halogen and trifluoromethyl independently, or R ¹¹ and R ^{12 may} be jointly formed by the nitrogen atom to which they are attached. A 4- to 7-membered nitrogen heterocyclic ring, wherein the 4- to 7-membered nitrogen heterocyclic ring may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and 4- to 7-membered heterocyclic ring selected from the group consisting of substituents, and L ² Represents a bond or (C ₁ -C ₄ ) -alkylene, R ¹³ represents a 5- to 9-membered nitrogen heterocyclic ring, which is connected via a ring carbon atom, wherein the 5- to 9-membered nitrogen heterocyclic ring may be Substituted by 1 to 5 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and benzyl , And the 5- to 9-membered nitrogen heterocyclic ring may be fused with a phenyl ring, and the phenyl ring itself may be substituted by halogen or (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ )-substituted by a substituent selected from the group consisting of alkoxy and trifluoromethyl, or represents adamantyl, R ⁴ represents hydrogen, and R ⁵ represents hydrogen, halogen, cyano, monofluoromethyl, Difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₂ -C ₄ ) -alkynyl, difluoromethoxy, Trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amine, 4- to 7-membered heterocyclic or 5- or 6-membered heteroaryl, R ⁶ represents hydrogen, cyano or halogen , And its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), wherein A represents CH ₂ or CH (CH ₃ ), and R ¹ represents phenyl, wherein phenyl can be independently Substituted with a substituent selected from the group consisting of fluorine, chlorine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, and the phenyl group is via (C ₃ -C ₆ ) -cycloalkyl, (C ₁ -C ₂ ) -alkoxy and trifluoromethoxy substituted with selected substituents, R ² represents hydrogen, trifluoromethyl, (C ₁ -C ₃ ) -alkyl or cyclopropyl, R ³ represents a group of the formula Where * is the point of connection with the carbonyl group, L ^1A is a bond, L ^1B is a bond, methyl or 1,2-ethylene, and L ^1C is a bond or methyl, where The methyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ is Represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, where (C ₁ -C ₆ ) -Alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl via 1 or 2 Selected from the group consisting of phenoxy and benzyloxy, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with one or two substituents selected from the group consisting of fluorine and chlorine, Wherein (C ₃ -C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and phenyl and 5 -Or 6-membered heteroaryl can be independently selected from fluorine, chlorine, cyano, nitro, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, -NH (CO) CH _3, methyl, vinyl, (C ₁ -C ₄₎ - group consisting of alkoxy and trifluoromethyl substituent selected from the substituent group , Where (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ together form a carbon atom of 3 to 6 -A membered carbocyclic or oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl or piperidinyl ring, wherein the 3- to 6-membered carbocyclic ring and oxonyl, tetrahydrofuranyl, tetra The hydropiperanyl, azido, pyrrolidinyl, and piperidinyl rings may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and methyl independently. R ⁹ represents hydrogen, cyano , 1,1,2,2-tetrafluoroethyl, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl Or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, 5-membered heteroaryl, phenyl, phenoxy and benzyloxy selected from the group consisting of phenyl , Phenoxy and benzyloxy may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein the 5-membered heteroaryl group may be benzo-fused or 5-membered heteroaryl Substituents, where 5- or 6-membered heteroaryl can be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C ₃ -C ₆ ) -cycloalkyl can be substituted with 1 or 2 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, and the phenyl group and 5- or 6-membered heteroaryl group thereof may be independently replaced by 1 or 2 Substituted with a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, trifluoromethoxy, difluoromethoxy, (C ₁ -C ₄ ) -alkoxy and trifluoromethyl, wherein ( C ₁ -C ₄ ) -alkoxy is substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ are carbon atoms connected to them to form a 3- to 6-membered carbon. Ring or oxo, tetrahydrofuranyl, tetrahydropiperanyl, azido, pyrrolidinyl or piperidinyl ring, wherein the 3- to 6-membered carbocyclic ring and oxo, tetrahydrofuranyl, tetrahydropiperan Amino, azino, pyrrolidinyl, and piperidinyl rings can be independently selected from fluorine and benzyl via 1 or 2 The substituents selected from the group consisting of methyl and methyl groups are subject to the limitation that both R ⁷ and R ⁹ groups cannot represent phenyl simultaneously, or that R ⁷ and R ⁹ are in common with the carbon atom and L ^1B group to which they are attached. Forms a cyclopentyl, cyclohexyl, aziridinyl, oxenyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropiperidinyl ring, subject to the restrictions R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups must not have more than one pair to form one of the above carbon- or heterocyclic rings. R ¹¹ represents hydrogen or (C ₁ -C ₃ ) -alkyl, in which (C ₁ -C ₃ ) -Alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, methoxy, and ethoxy, and R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, cyclobutyl, phenyl or benzyl, wherein (C ₁ -C ₄ ) -alkyl may be independently selected from fluorine, trifluoromethyl, A substituent selected from the group consisting of hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and the phenyl and benzyl groups thereof may be independently replaced by fluorine, chlorine and trifluoro through 1 to 3 Selected from the group consisting of methyl groups, or R ¹¹ and R ¹² is a nitrogen atom, pyrrolidinyl, piperidinyl, morpholinyl, piperidine Group, timorpholinyl or 1,1-dioxotimorpholinyl ring, wherein aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl Group, timorpholinyl group and 1,1-dioxotimorpholinyl ring can be independently selected from fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutane through 1 or 2 Selected from the group consisting of aziridinyl, pyrrolidinyl, and piperidinyl, and L ² represents a bond, methylidene, or 1,1-ethylene, and R ¹³ represents pyrrolidine , Piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1 ] Octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl, and those linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indolyl, 8-aza Bicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen R ⁵ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, monofluoromethyl, ethynyl or cyclopropyl, R ⁶ represents hydrogen or fluorine, and its N-oxides and salts Compounds, solvates, N-oxide salts and N-oxide and salt solvates.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents phenyl, wherein phenyl is substituted with 1 to 2 fluorines, and phenyl is substituted by 1 Substituted by a substituent selected from the group consisting of cyclopropyl and methoxy, R ² represents a trifluoromethyl, methyl, ethyl or cyclopropyl group, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or methyl, and L ^1C represents a bond or methyl, where methyl can pass through 1 or 2 Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents hydrogen, trifluoromethyl, (C _1- C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and trifluoromethyl via 1 or 2 Selected from the group consisting of phenyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, and benzyloxy, wherein phenyl, phenoxy, and benzyloxy may themselves be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine, trifluoromethyl, methyl and The substituents selected from the group consisting of ethyl groups, and their phenyl groups may be independently substituted by fluorine, chlorine, cyano, nitro, difluoromethoxy, trifluoromethoxy, -NH Selected substitutions from the group consisting of (CO) CH ₃ , ethynyl, ethoxy and trifluoromethyl Group substitution, in which the ethoxy group may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ are carbon atoms connected to them to form a 3- to 6-membered carbocyclic ring or oxygen Fluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic ring and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, nitrogen The fluorenyl, pyrrolidinyl, and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents hydrogen, cyano, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, Selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy and benzyloxy, wherein phenyl, phenoxy and benzyl The oxy group itself may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine or trifluoromethyl via 1 or 2 Selected from the group consisting of methyl, methyl and ethyl, and benzene The group may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, trifluoromethoxy, difluoromethoxy, ethoxy, and trifluoromethyl, independently of each other. The oxy group may be substituted by a hydroxy group. R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbocyclic or oxo, tetrahydrofuranyl group together with the carbon atom to which they are attached. , Tetrahydropiperanyl, azetino, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxonyl, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidin And the piperidinyl ring may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and methyl independently of each other, with the limitation that R ⁷ and R ⁹ groups cannot simultaneously represent phenyl, Or R ⁷ and R ⁹ together form a cyclopentyl group, a cyclohexyl group, an azino group, an oxo group, a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, or a tetrahydropiperidinyl group together with the carbon atom and L ^1B group to which Ring, the restriction is that each of the R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot form one or more of the above carbon- or heterocyclic rings at the same time, R ¹¹ represents Hydrogen or (C ₁ -C ₃ ) -alkyl, in which (C ₁ -C ₃ ) -alkyl may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and trifluoromethyl, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl or cyclobutyl, wherein (C ₁ -C ₄ ) -alkyl can be independently replaced by fluorine and trifluoro via 1 or 2 A substituent selected from the group consisting of methyl groups is substituted, or R ¹¹ and R ¹² form a nitrogen atom, pyrrolidyl, piperidinyl, or morpholinyl ring together with the nitrogen atom to which they are attached, wherein the nitrogen atom, The pyrrolidinyl, piperidinyl, and morpholinyl rings may be substituted with one or two groups selected from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl. Group substitution, and L ² represents a bond or a methyl group, and R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- Tetrahydroquinolyl, indolyl, 8-azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] Heptyl or linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 8-azabicyclo [3.2. 1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen , R ⁵ represents hydrogen, fluorine, chlorine, methyl, ethyl, monofluoromethyl, ethynyl or cyclopropyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, N- Oxide salts and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , R ¹ represents phenyl, wherein phenyl is substituted with 1 to 2 fluorines, and phenyl is substituted via a ring Selected from the group consisting of propyl and methoxy, R ² represents methyl, and R ³ represents a group of the formula or , Where * represents the point connected to the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and the phenyl group may be independently substituted by fluorine, difluoromethoxy, trifluoromethoxy through 1 or 2 Group selected from the group consisting of alkyl, vinyl, ethoxy and chlorine, wherein ethoxy may be substituted by hydroxyl, R ⁸ represents hydrogen, methyl or ethyl, R ⁹ represents hydrogen, cyano, Trifluoromethyl, (C ₁ -C ₆ ) -alkyl, cyclopropyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, tri Fluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and the phenyl group can be independently replaced by fluorine or trifluoromethoxy through 1 or 2 Group selected from the group consisting of alkyl, difluoromethoxy, ethoxy and chlorine, wherein Ethoxy may be substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ together form a 3- to 6-membered carbocyclic ring or oxo ring, The restriction is that R ⁷ and R ⁹ groups cannot represent phenyl simultaneously, or that R ⁷ and R ⁹ are a carbon atom and L ^1B group connected to each other to form a cyclopentyl or cyclohexyl ring. The restrictions are different. R ⁷ and R ⁸ , R ⁹ and R ^10, and R ⁷ and R ⁹ groups must not have more than one pair at the same time to form one of the above carbon- or heterocyclic rings. R ¹¹ represents hydrogen, R ¹² represents hydrogen, and L Line ² represents a bond, and R ¹³ represents piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, or 1,2,3,4-tetrahydroquinolin-4-yl, of which Pyridin-2-yl, piperidin-3-yl and piperidin-4-yl may be substituted with 1 to 5 substituents selected from the group consisting of trifluoromethyl and methyl independently of each other, and 1, 2,3,4-tetrahydroquinolin-4-yl may be substituted by fluorine or trifluoromethyl, R ⁴ represents hydrogen, and R ⁵ represents hydrogen, fluorine, chlorine, monofluoromethyl, ethynyl or methyl , R ⁶ represents hydrogen, and its N-oxides, salts, solvates, N-oxide salts and N-oxides and salts Of solvates.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, wherein (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be substituted by 1 to 4 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and (C ₁ -C ₄ ) -alkyl, and the phenyl group thereof may be independently substituted by halogen, cyano, Monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, (C ₃ -C ₆ ) -cycloalkyl, A substituent selected from the group consisting of difluoromethoxy and trifluoromethoxy, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl Or trifluoromethyl, R ³ represents a group of the formula or

Where * represents the point of attachment to the carbonyl group L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene can be independent of each other via 1 to 3 Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, and L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy group selected by substituents, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C _2- C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, cyano, 5- to 10-membered heteroaryl, naphthyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl may be After 1 to 3 each independently of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ )- alkoxy - carbonyl group, (C ₁ -C ₄₎ - alkylsulfonyl group, a phenyl group, a phenoxy group and benzyloxy group consisting of selected from Substituents, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄₎ - alkoxy substituted to substituent, wherein (C ₃ -C ₇₎ - cycloalkyl The alkyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, and (C ₁ -C ₄ ) -alkoxy, independently of each other. , And its phenyl and 5- to 10-membered heteroaryl groups can be independently selected from halogen, cyano, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy, Fluoromethoxy, -NH (CO) CH ₃ , (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkyl, (C ₁ -C ₄ ) -alkenyl, (C ₁ -C ₄ ) -alkylsulfonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, and (C ₁ -C ₄ ) -alkoxy, selected from the group consisting of (C _1- C ₄ ) -alkoxy may be substituted by a hydroxyl group, and two adjacent carbon atoms of the phenyl group may be substituted by a difluoromethylene dioxy bridge. R ⁸ represents hydrogen or (C ₁ -C ₄ )- Alkyl, or R ⁷ and R ⁸ are carbon atoms to which they are attached to form a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring and 4- The 7-membered heterocycle itself can be independently replaced by fluorine through 1 or 2 (C ₁ -C ₄₎ - alkyl group selected from the group consisting of the substituents, R ⁹ represents hydrogen system, cyano, (C ₁ -C ₆₎ - alkyl, (C ₂ -C ₆₎ - alkenyl , (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, 5- to 10-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkyl may be 1 to 3 each independently of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, cyano, (C ₁ -C ₄ ) -alkoxy, ( C ₁ -C ₄₎ - alkoxycarbonyl, (C ₁ -C ₄₎ - alkyl sulfo group consisting of acyl, 5- or 6-membered heteroaryl, phenyl, phenoxy and benzyloxy in Selected substituent substitutions, where phenyl, phenoxy and benzyloxy may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, of which 5- or 6-membered heteroaryl The group may be benzo-fused or substituted with 5- or 6-membered heteroaryl, wherein 5- or 6-membered heteroaryl may be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C ₃ -C ₇ ) -cycloalkyl can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy via 1 or 2 The selected group in the composition group is substituted, and the phenyl group and the 5- to 10-membered heteroaryl group may be substituted by 1 to 3 Independently of one another by halogen, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄₎ - alkyl, (C ₁ -C ₄₎ - Selected substituents selected from the group consisting of cycloalkyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl, and (C ₁ -C ₄ ) -alkylsulfonyl Substitution, in which (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, and the phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms, and R ¹⁰ represents hydrogen or (C ₁ -C ₄ ) -alkyl, or R ⁹ and R ¹⁰ are a carbon atom to which they are attached to form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring, wherein the 3- to The 7-membered carbocyclic ring and the 4- to 7-membered heterocyclic ring itself may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, benzyl and (C ₁ -C ₄ ) -alkyl independently of each other, The limitation is that R ⁷ and R ⁹ groups cannot represent phenyl groups at the same time, or R ⁷ and R ⁹ are connected to the carbon atom and L ^1B group to form a 3- to 7-membered carbocyclic ring or 4- to 7- A membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring may be independently selected from (C ₁ -C ₄ ) -alkyl, fluorine, hydroxyl, and (C ₁ -C ₄ ) -alkoxy via 1 or 2 Selected from the group Substituted with a substituent, with the proviso that respective R ⁷ and R ^8, R ⁹ and R ¹⁰ and R ⁷ and R ⁹ can not have a group of one or more pairs of carbon formed simultaneously - or heterocycle, R ¹¹ represents hydrogen or based (C ₁ -C ₄ ) -alkyl, wherein (C ₁ -C ₄ ) -alkyl may be independently selected from fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkane through 1 to 3 Substitutes selected from the group consisting of oxy groups, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, where (C _1- C ₆ ) -alkyl may be substituted through 1 to 3 substituents independently selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy Substitution, and the phenyl and benzyl groups thereof may be substituted by 1 to 3 substituents selected from the group consisting of halogen and trifluoromethyl independently, or R ¹¹ and R ^{12 may} be jointly formed by the nitrogen atom to which they are attached. A 4- to 7-membered nitrogen heterocyclic ring, wherein the 4- to 7-membered nitrogen heterocyclic ring may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and 4- to 7-membered heterocyclic ring selected from the group consisting of substituents, and L ² Represents a bond or (C ₁ -C ₄ ) -alkylene, R ¹³ represents a 5- to 9-membered nitrogen heterocyclic ring, which is connected via a ring carbon atom, wherein the 5- to 9-membered nitrogen heterocyclic ring may be Substituted by 1 to 5 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and benzyl , And the 5- to 9-membered nitrogen heterocyclic ring may be fused with a phenyl ring, and the phenyl ring itself may be subjected to 1 or 2 by halogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ )-selected from the group consisting of alkoxy and trifluoromethyl, or represents adamantyl, R ⁴ represents hydrogen, R ⁵ represents monofluoromethyl, difluoromethyl, trifluoro Methyl, (C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₆ ) -cycloalkyl, difluoromethoxy, trifluoromethoxy, ( C ₁ -C ₄ ) -alkoxy, amine, 4- to 7-membered heterocyclic or 5- or 6-membered heteroaryl, R ⁶ represents hydrogen, cyano or halogen, and its N-oxide , Salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆₎ - cycloalkyl, or phenyl, wherein (C ₄ -C ₆₎ - alkyl which may be substituted by fluorine High 6, wherein (C ₄ -C ₆₎ - cycloalkyl may be substituted with 1 or 2 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and methyl, and the phenyl group thereof may be independently substituted by fluorine, chlorine, cyano, methoxy, and ethoxy through 1 to 4 Group, substituted with a substituent selected from the group consisting of difluoromethyl, trifluoromethyl, (C ₃ -C ₆ ) -cycloalkyl and methyl, R ² represents hydrogen, trifluoromethyl, (C ₁ -C ₃ ) -alkyl or cyclopropyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, methyl or 1,2-ethylene, and L ^1C represents a bond or methyl, where The methyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ is Represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, where (C ₁ -C ₆ ) -Alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl via 1 or 2 Selected from the group consisting of phenoxy and benzyloxy, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with one or two substituents selected from the group consisting of fluorine and chlorine, Wherein (C ₃ -C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and phenyl and 5 -Or 6-membered heteroaryl can be independently selected from fluorine, chlorine, cyano, nitro, methyl, ethylene via 1 or 2 , Difluoromethoxy, _{trifluoromethoxy, -NH (CO) CH 3,} (C 1 -C 4) - alkoxy and trifluoromethyl group consisting of the substituents selected from substituent group, wherein (C _1- C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ together form a 3- to 6-membered carbocyclic ring Or an oxo, tetrahydrofuranyl, tetrahydropiperanyl, azido, pyrrolidinyl, or piperidinyl ring, wherein the 3- to 6-membered carbocyclic and oxo, tetrahydrofuran, tetrahydropiperanyl , Azetidinyl, pyrrolidinyl, and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other, R ⁹ represents hydrogen, cyano, 1,1 , 2,2-tetrafluoroethyl, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl Where (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C _1- C ₄₎ - group consisting of alkoxy, 5-membered heteroaryl, phenyl, phenoxy and benzyloxy substituents selected from the substituent group, wherein the phenyl, phenoxy, and Group may itself be substituted with 1 or 2 substituents from the group consisting of fluorine and chlorine substituents selected from the substituent group, wherein the 5-membered heteroaryl groups may be benzo-fused 5-membered heteroaryl or with a substituted aryl group, wherein (C ₃ -C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, and phenyl and 5- or 6- Heteroaryl groups can be independently selected from fluorine, chlorine, cyano, methyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy and trifluoro A substituent selected from the group consisting of methyl groups, in which (C ₁ -C ₄ ) -alkoxy group may be substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ are related to it. The linked carbon atoms together form a 3- to 6-membered carbocyclic or oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidinyl, or piperidinyl ring, wherein the 3- to 6-membered Carbocyclic and oxonyl, tetrahydrofuranyl, tetrahydropiperanyl, azepinyl, pyrrolidinyl, and piperidinyl rings may be in one or two groups independently of each other consisting of fluorine, benzyl, and methyl the selected substituents, with the proviso that R ⁷ and R ⁹ groups can not When represents a phenyl group, or R ⁷ and R ⁹ lines with the carbon atoms, and L ^1B groups concatenate together form a cyclopentyl group, a cyclohexyl group, a nitrogen Ta group, an oxygen Da group, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or The tetrahydropiperidinyl ring is subject to the limitation that each of the R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot form one or more of the above carbon- or heterocyclic rings simultaneously, R ¹¹ represents hydrogen or (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl may be independently selected from fluorine, trifluoromethyl, hydroxyl, and methoxy via 1 or 2 And an ethoxy group, and R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, cyclobutyl, phenyl, or benzyl, wherein (C _1- C ₄ ) -alkyl may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, And its phenyl and benzyl groups may be substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine and trifluoromethyl, or R ¹¹ and R ^{12 may} form a Azino, pyrrolidinyl, piperidinyl, morpholinyl Pipe Group, timorpholinyl or 1,1-dioxotimorpholinyl ring, wherein aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl Can be independently selected from fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl via 1 or 2 , Selected from the group consisting of azepine, pyrrolidinyl, and piperidinyl, and L ² represents a bond, methyl or 1,1-ethylene, and R ¹³ represents pyrrolidinyl , Piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1] Octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-aza Bicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen R ⁵ represents monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₆ )- Cycloalkyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, 5- to 6-membered heterocyclic or 5- or 6-membered heteroaryl, R ⁶ series Represents hydrogen or fluorine, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl Or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, where (C ₄ -C ₆ ) -cycloalkyl can be independently replaced by fluorine or trifluoromethyl via 1 or 2 And substituents selected from the group consisting of methyl and methyl, and the phenyl group thereof may be selected from 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyclopropyl, methoxy and methyl Substitution, R ² represents a trifluoromethyl, methyl, ethyl or cyclopropyl group, and R ³ represents a group of the formula or , Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass through 1 or 2 Each independently selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents hydrogen, trifluoromethyl, ( C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and trifluoro via 1 or 2 Methyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy and benzyloxy selected from the group consisting of substituents, in which phenyl, phenoxy and benzyloxy may themselves Substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently selected from fluorine, trifluoromethyl, methyl by 1 or 2 And the ethyl group is substituted by a selected substituent, and its phenyl group may be independently substituted by fluorine, chlorine, cyano, nitro, vinyl, difluoromethoxy, trifluoromethoxy through 1 or 2 group, the group consisting of CH _3, ethoxy and trifluoromethyl -NH (CO) selected from the take Substituent group, wherein the ethoxy may be substituted with hydroxy, the carbon-based R ⁸ represents hydrogen atom, methyl or ethyl, or R ⁷ and R ⁸ lines connected thereto together form a 3- to 6-membered carbocyclic or oxygen Fluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, or piperidinyl rings, of which 3- to 6-membered carbocyclic and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azepine Group, pyrrolidinyl, and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents hydrogen, cyano, trifluoromethyl, ( C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano and fluorine via 1 or 2 , Trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy and benzyloxy selected from the group consisting of phenyl, phenoxy and benzyloxy The basic body can be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl can be independently substituted by fluorine or trifluoromethyl through 1 or 2 Selected from the group consisting of methyl, methyl and ethyl, and its benzene The group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, difluoromethoxy, trifluoromethoxy, ethoxy, and trifluoromethyl, independently of each other. The oxy group may be substituted by a hydroxy group. R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbocyclic or oxo, tetrahydrofuranyl group together with the carbon atom to which they are attached. , Tetrahydropiperanyl, azetino, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxonyl, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidin And the piperidinyl ring may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and methyl independently of each other, with the limitation that R ⁷ and R ⁹ groups cannot simultaneously represent phenyl, Or R ⁷ and R ⁹ together form a cyclopentyl group, a cyclohexyl group, an aziridinyl group, an oxenyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, or a tetrahydropiperidinyl group together with the carbon atom and the L ^1B group to which they are attached. Ring, the restriction is that each of the R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot form one or more of the above carbon- or heterocyclic rings at the same time, R ¹¹ represents Hydrogen or (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and trifluoromethyl, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl or cyclobutyl, wherein (C ₁ -C ₄ ) -alkyl can be independently replaced by fluorine and trifluoro via 1 or 2 A substituent selected from the group consisting of methyl groups is substituted, or R ¹¹ and R ¹² form a nitrogen atom, pyrrolidyl, piperidinyl, or morpholinyl ring together with the nitrogen atom to which they are attached, wherein the nitrogen atom, The pyrrolidinyl, piperidinyl, and morpholinyl rings may be substituted with one or two groups selected from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl. Group substitution, and L ² represents a bond or a methyl group, and R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- Tetrahydroquinolyl, indolyl, 8-azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] Heptyl or linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 8-azabicyclo [3.2. 1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen R ⁵ represents monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, ethynyl, methoxy, morpholinyl, R ⁶ represents hydrogen, and its N-oxides and salts Compounds, solvates, N-oxide salts and N-oxide and salt solvates.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula

Where # represents the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent hydrogen, fluorine, methoxy, cyclopropyl or chlorine, and the restriction is at least two R ¹⁴ , R ¹⁵ The R ¹⁶ group is not hydrogen, R ² represents a methyl group, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, ( C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and the phenyl group can be independently substituted by fluorine, vinyl, difluoromethoxy, trifluoro through 1 or 2 A substituent selected from the group consisting of methoxy, ethoxy and chlorine, wherein ethoxy may be substituted by hydroxyl, R ⁸ represents hydrogen, methyl or ethyl, R ⁹ represents hydrogen, cyano, tris Fluoromethyl, (C ₁ -C ₆ ) -alkyl, cyclopropyl or phenyl, where (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoro via 1 or 2 Methyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and phenyl groups selected from the substituents, and the phenyl group may be independently substituted by fluorine or difluoromethoxy through 1 or 2 , Trifluoromethoxy, ethoxy and chlorine selected from the group consisting of The oxy group may be substituted by a hydroxy group. R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbocyclic ring or oxo ring together with the carbon atom to which they are attached. The restriction is that R ⁷ and R ⁹ groups cannot represent phenyl simultaneously, or that R ⁷ and R ⁹ are a carbon atom and a L ^1B group connected to each other to form a cyclopentyl or cyclohexyl ring. The restriction is that each R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot have more than one pair forming one of the above carbon- or heterocyclic rings simultaneously, R ¹¹ represents hydrogen, R ¹² represents hydrogen, and L ² represents a bond, R ¹³ represents piperidin-2-yl, piperidin-3-yl, piperidin-4-yl or 1,2,3,4-tetrahydroquinolin-4-yl, among which piperidin-2-yl, piperidin Pyridin-3-yl and piperidin-4-yl may be substituted with 1 to 5 substituents selected from the group consisting of trifluoromethyl and methyl independently of each other, and 1,2,3,4-tetra Hydroquinoline-4-yl may be substituted by fluorine or trifluoromethyl. R ⁴ represents hydrogen, and R ⁵ represents monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, ethynyl, and methyl. Oxygen, morpholinyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, and N-oxide salts And solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, wherein (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be substituted by 1 to 4 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, and (C ₁ -C ₄ ) -alkyl, and the phenyl group thereof may be independently replaced by halogen, cyano, Monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, (C ₃ -C ₆ ) -cycloalkyl, A substituent selected from the group consisting of difluoromethoxy and trifluoromethoxy, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl Or trifluoromethyl, R ³ represents a group of the formula

Where * represents the point of attachment to the carbonyl group L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene can be independent of each other via 1 to 3 Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, and L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy group selected substituents, R ⁷ represents (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkynyl, cyano or phenyl, Wherein (C ₁ -C ₆ ) -alkyl may be substituted by 1 to 3 groups selected independently from each other consisting of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy and phenoxy Group substitution, where the phenoxy group can be substituted with 1 to 3 halogen substituents, where the phenyl group can be independently substituted with 1 or 2 by cyano, nitro, difluoromethoxy, trifluoromethoxy, ( C ₁ -C ₄ ) -alkoxy, -NH ( CO) CH ₃ and (C ₁ -C ₄ ) -alkenyl group consisting of selected substituents, in which (C ₁ -C ₄ ) -alkoxy is substituted with hydroxyl, R ⁸ is hydrogen or (C _1- C ₄ ) -alkyl, R ⁹ represents hydrogen, cyano, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl (C ₃ -C ₇ ) -cycloalkyl, 5- to 10-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, di Fluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxy, cyano, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl , (C ₁ -C ₄ ) -alkylsulfonyl, 5- or 6-membered heteroaryl, phenyl, phenoxy and benzyloxy selected from the group consisting of phenyl, benzene The oxy and benzyloxy groups may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, where the 5- or 6-membered heteroaryl group may be benzo-fused or substituted with 5- Or 6-membered heteroaryl substitution, where 5- or 6-membered heteroaryl can be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C ₃ -C ₇ ) -cycloalkyl 1 or 2 may be independently of one another by fluorine, trifluoromethyl, (C ₁ -C ₄₎ - alkyl and (C ₁ -C ₄₎ - alkyl Selected from the group consisting of substituents, and its phenyl and 5- to 10-membered heteroaryl groups may be independently selected from halogen, cyano, difluoromethyl, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl are substituted with a selected substituent, wherein (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, And its phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms, R ¹⁰ represents hydrogen or (C ₁ -C ₄ ) -alkyl, or R ⁹ and R ¹⁰ The linked carbon atoms together form a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring and the 4- to 7-membered heterocyclic ring can themselves pass through 1 or Two substituents independently selected from the group consisting of fluorine, benzyl and (C ₁ -C ₄ ) -alkyl are substituted, the limitation is that both R ⁷ and R ⁹ groups cannot represent phenyl simultaneously, R ¹¹ represents hydrogen or (C ₁ -C ₄ ) -alkyl, wherein (C ₁ -C ₄ ) -alkyl may be independently selected from fluorine, trifluoromethyl, hydroxyl and (C _1- C ₄ ) -alkoxy R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, where (C ₁ -C ₆ ) -alkyl may be substituted with 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, independently of each other. , And its phenyl and benzyl groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen and trifluoromethyl, or R ¹¹ and R ^{12 may} form a 4- to 7-membered nitrogen heterocyclic ring, wherein the 4- to 7-membered nitrogen heterocyclic ring may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, ( C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and 4- to 7-membered heterocyclic ring selected from the group consisting of substituents, and L ² represents a bond Or (C ₁ -C ₄ ) -alkylene, R ¹³ represents a 5- to 9-membered nitrogen heterocyclic ring, which is connected via a ring carbon atom, wherein the 5- to 9-membered nitrogen heterocyclic ring may be 5 independently of one another by fluorine, trifluoromethyl, (C ₁ -C ₄₎ - alkyl, (C ₃ -C ₇₎ - cycloalkyl and benzyl group consisting of the substituents selected from, Wherein the 5- to 9-membered nitrogen heterocycle may be fused to a phenyl ring, the phenyl ring can itself be substituted with 1 or 2 halogen, (C ₁ -C ₄₎ - alkyl, (C ₁ -C ₄₎ -Substituted by a substituent selected from the group consisting of alkoxy and trifluoromethyl, or represents adamantyl, R ⁴ represents hydrogen, and R ⁵ represents hydrogen, halogen, cyano, monofluoromethyl, difluoro Methyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₆ ) -ring Alkyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amine, 4- to 7-membered heterocyclic or 5- or 6-membered heteroaryl, R ⁶ represents hydrogen, cyano or halogen, and its N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆₎ - cycloalkyl, or phenyl, wherein (C ₄ -C ₆₎ - alkyl which may be substituted by fluorine High 6, wherein (C ₄ -C ₆₎ - cycloalkyl may be substituted with 1 or 2 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and methyl, and the phenyl group thereof may be independently substituted by fluorine, chlorine, cyano, methoxy, and ethoxy through 1 to 4 Group, difluoromethyl group, trifluoromethyl group, (C ₃ -C ₆ ) -cycloalkyl group and methyl group. R ² represents hydrogen, trifluoromethyl group, (C ₁ -C ₃ ) -alkyl and cyclopropyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, methyl or 1,2-ethylene, and L ^1C represents a bond or methyl, where The methyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ is Represents (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkynyl, cyano or phenyl, wherein (C ₁ -C ₆ ) -alkyl is independently selected from 1 to 3 by Selected from the group consisting of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and phenoxy, wherein phenoxy may be substituted by 1 to 3 fluorines, and phenyl may be substituted by 1 or 2 each independently of cyano, nitro, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, -NH (CO) CH ₃ and (C _1- C ₄ ) -Alkenyl group consisting of selected substituents, in which (C ₁ -C ₄ ) -alkoxy may be substituted by hydroxyl, R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl, R ⁹ represents hydrogen, cyano, 1,1,2,2-tetrafluoroethyl, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl Or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, ( C ₁ -C ₄ ) -alkoxy, 5-membered heteroaryl, phenyl, phenoxy and benzyloxy selected from the group consisting of phenyl, phenoxy and benzyloxy themselves Can be substituted with 1 or 2 substituents selected from the group consisting of fluorine and chlorine, where 5-membered heteroaryl can be benzo-fused or substituted with 5-membered heteroaryl, where (C ₃ -C ₆ ) -Cycloalkyl can be substituted by 1 or 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, and phenyl and 5- or 6-membered heteroaryl The radical may be composed of 1 or 2 independently of each other by fluorine, chlorine, cyano, methyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy and trifluoromethyl Selected substituents in the group, in which (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ are the carbons connected to it Atoms together form a 3- to 6-membered carbocyclic or oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azepine , Pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxo, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidinyl, and piperidinyl rings can be passed through 1 or 2 substituents selected from the group consisting of fluorine, benzyl and methyl independently of each other, with the limitation that both R ⁷ and R ⁹ groups cannot represent phenyl, or R ¹¹ is hydrogen or (C ₁ -C ₃ ) -Alkyl, wherein (C ₁ -C ₃ ) -Alkyl may be composed of fluorine, trifluoromethyl, hydroxyl, methoxy, and ethoxy via 1 or 2 independently of each other. Substituted by selected substituents in the group, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, cyclobutyl, phenyl or benzyl, of which (C ₁ -C ₄ ) -alkyl Can be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and phenyl and benzyl The group can be substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine and trifluoromethyl independently, or R ¹¹ and R ¹² together form a nitrogen atom, pyrrolidine Base, piperidinyl, morpholinyl, piperidine Group, timorpholinyl or 1,1-dioxotimorpholinyl ring, wherein aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl Can be independently selected from fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl via 1 or 2 , Selected from the group consisting of azepine, pyrrolidinyl, and piperidinyl, and L ² represents a bond, methyl or 1,1-ethylene, and R ¹³ represents pyrrolidinyl , Piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1] Octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-aza Bicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen R ⁵ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, monofluoromethyl, methoxy, ethynyl, or cyclopropyl, R ⁶ represents hydrogen or fluorine, and its N- Oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl Or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, where (C ₄ -C ₆ ) -cycloalkyl can be independently replaced by fluorine or trifluoromethyl via 1 or 2 And substituents selected from the group consisting of methyl and methyl, and the phenyl group thereof may be selected from 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyclopropyl, methoxy and methyl Substitution, R ² represents a trifluoromethyl, methyl, ethyl or cyclopropyl group, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass through one or two methyl groups. Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents (C ₁ -C ₄ ) -alkane , Cyano or phenyl, wherein (C ₁ -C ₄ ) -alkyl can be substituted with 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl and phenoxy, wherein The phenoxy group may be substituted by 1 to 3 fluorine substituents, wherein the phenyl group may be independently substituted by 1 or 2 by cyano, difluoromethoxy, trifluoromethoxy, ethoxy, -NH (CO ) Substituted by a substituent selected from the group consisting of CH ₃ and vinyl, wherein ethoxy is substituted with hydroxyl, R ⁸ represents hydrogen, and R ⁹ represents hydrogen, cyano, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl may be independently selected from cyano, fluorine, trifluoromethyl via 1 or 2 group, hydroxy, (C ₁ -C ₄₎ - group consisting of alkoxy, phenyl, phenoxy and benzyloxy in Of the substituents, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with 1 or 2 substituents from the group consisting of fluorine and chlorine substituents selected from the substituent group, wherein (C ₃ -C ₆₎ - cycloalkyl, It may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and the phenyl group thereof may be substituted by fluorine, chlorine, Difluoromethoxy, trifluoromethoxy, ethoxy, cyano and trifluoromethyl are selected from the group consisting of substituents, in which ethoxy may be substituted by hydroxyl, R ¹⁰ represents hydrogen, methyl Or ethyl, or R ⁹ and R ¹⁰ together form a 3- to 6-membered carbocyclic or oxo group, tetrahydrofuranyl, tetrahydropiperanyl, azino, pyrrolidinyl or A piperidinyl ring, wherein the 3- to 6-membered carbocyclic ring and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, and piperidinyl rings may be independent of each other through 1 or 2 It is substituted by a substituent selected from the group consisting of fluorine, benzyl and methyl, and the restriction is that both R ⁷ and R ⁹ groups cannot represent phenyl, or R ¹¹ represents hydrogen or (C ₁ -C ₃ )-alkyl Wherein the (C ₁ -C ₃₎ - alkyl group may be substituted with 1 or 2 groups independently of one another by fluorine and the trifluoromethyl substituent selected from the substituent group, R ¹² represents hydrogen system, (C ₁ -C ₄₎ -Alkyl, cyclopropyl or cyclobutyl, wherein (C ₁ -C ₄ ) -alkyl may be substituted with 1 or 2 substituents selected from the group consisting of fluoro and trifluoromethyl independently of each other, or R ¹¹ and R ¹² together form a nitrogen atom, pyrrolidinyl, piperidinyl, or morpholinyl ring with the nitrogen atom to which R ¹¹ and R ¹² are bonded. It may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl, and L ² represents a bond or dyne R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indolinyl, 8- Azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl or linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 8-azabicyclo [3.2. 1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen , R ⁵ represents hydrogen, fluorine, chlorine, methyl, ethyl, monofluoromethyl, methoxy, ethynyl, or cyclopropyl, R ⁶ represents hydrogen, and its N-oxides, salts, and solvents Compounds, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), wherein A represents CH ₂ and R ¹ represents phenyl of the formula Where # is the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ are independently of each other hydrogen, fluorine, methoxy, cyclopropyl or chlorine, and the restriction is at least two R ¹⁴ , R ¹⁵ , R ¹⁶ is not hydrogen, R ² represents methyl, and R ³ represents a group of the formula Where * represents the point of attachment to the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, and R ⁷ represents (C ₁ -C ₄ ) -alkyl, cyano or Phenyl, where (C ₁ -C ₄ ) -alkyl is substituted with fluorine up to five times, and phenyl is substituted with cyano, difluoromethoxy, trifluoromethoxy, ethoxy, -NH ( CO) CH ₃ or vinyl substitution, in which ethoxy is substituted by hydroxyl, R ⁸ represents hydrogen, R ⁹ represents hydrogen, cyano, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, cyclic Propyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy via 1 or 2 And selected from the group consisting of phenyl, and its phenyl group may be independently composed of 1 or 2 groups consisting of fluorine, difluoromethoxy, trifluoromethoxy, ethoxy, and chlorine The selected substituent is substituted, in which the ethoxy group may be substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl, or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbon atom together. Da carbocyclic ring or oxygen, with the proviso that R ⁷ and R ⁹ group is not contemporary Phenyl, R ¹¹ represents hydrogen system, R ¹² represents a hydrogen system, and L ² represents a bond system, R ¹³ are representatives of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl or 1, 2,3,4-tetrahydroquinolin-4-yl, in which piperidin-2-yl, piperidin-3-yl and piperidin-4-yl can be independently selected from trifluoromethyl groups through 1 to 5 And a methyl group, and the 1,2,3,4-tetrahydroquinolin-4-yl group may be substituted by fluorine or trifluoromethyl, R ⁴ represents hydrogen, and R ⁵ represents Represents hydrogen, fluorine, chlorine, monofluoromethyl, ethynyl or methyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, N-oxide salts, and N-oxides and Solvates of salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, wherein (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be substituted by 1 to 4 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and (C ₁ -C ₄ ) -alkyl, and the phenyl group thereof may be independently substituted by halogen, cyano, Monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, (C ₃ -C ₆ ) -cycloalkyl, A substituent selected from the group consisting of difluoromethoxy and trifluoromethoxy, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl Or trifluoromethyl, R ³ represents a group of the formula or

Where * represents the point of attachment to the carbonyl group L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene can be independent of each other via 1 to 3 Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, and L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy group selected by substituents, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C _2- C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, cyano, 5- to 10-membered heteroaryl, naphthyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl may be After 1 to 3 each independently of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ )- alkoxy - carbonyl group, (C ₁ -C ₄₎ - alkylsulfonyl group, a phenyl group, a phenoxy group and benzyloxy group consisting of selected from Substituents, wherein phenyl, phenoxy and benzyloxy may be itself or 3 halogen (C ₁ -C ₄₎ with 1 to - substituted alkoxy substituent, wherein (C ₃ -C ₇₎ - cycloalkyl The group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy, And its phenyl and 5- to 10-membered heteroaryl groups can be independently selected from halogen, cyano, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoro through 1 to 3 Methoxy, -NH (CO) CH ₃ , (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkyl, (C ₁ -C ₄ ) -alkenyl, (C _1- Selected from the group consisting of C ₄ ) -alkylsulfonyl, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxy, wherein (C ₁ -C ₄ ) -Alkoxy may be substituted by a hydroxyl group, and two adjacent carbon atoms of the phenyl group may be substituted by a difluoromethylene dioxy bridge, and R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkane Or R ⁷ and R ⁸ together form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring with the carbon atom to which they are attached, wherein the 3- to 7-membered carbocyclic ring and 4- to The 7-membered heterocyclic ring itself can be independently (C ₁ -C ₄₎ - selected from the group of consisting of alkyl substituents, ⁹ are representatives of R (C ₁ -C ₆₎ - alkyl, cyano or phenyl, where (C ₁ -C ₆₎ - Alkyl is independently selected from fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 5- or 6-membered heteroaryl, phenoxy and Substituted by a substituent selected from the group consisting of benzyloxy, wherein phenoxy is substituted with 1 to 3 halogen substituents, wherein benzyloxy may be substituted with 1 to 3 halogen substituents, of which 5- or 6-membered Heteroaryl is substituted by 5- or 6-membered heteroaryl, wherein 5- or 6-membered heteroaryl is substituted by (C ₁ -C ₄ ) -alkyl, and phenyl is substituted by 1 or 2 Independently selected from the group consisting of cyano, difluoromethoxy, trifluoromethoxy and (C ₁ -C ₄ ) -alkoxy, wherein (C ₁ -C ₄ ) -alkane The oxy group is substituted by a hydroxyl group, R ¹⁰ represents hydrogen or (C ₁ -C ₄ ) -alkyl, and R ¹¹ represents hydrogen or (C ₁ -C ₄ ) -alkyl, of which (C ₁ -C ₄ )- Alkyl groups may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy groups, and R ¹² represents hydrogen , (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, wherein (C ₁ -C ₆ ) -alkyl may be independently from each other through 1 to 3 Substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and the phenyl and benzyl groups thereof may be independent of each other through 1 to 3 Substituted by a substituent selected from the group consisting of halogen and trifluoromethyl, or R ¹¹ and R ¹² together form a 4- to 7-membered nitrogen heterocyclic ring with the nitrogen atom to which they are attached, where the 4- to 7 -Member nitrogen heterocycles may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and 4- to 7-membered heterocyclic ring selected from the group consisting of substituents, and L ² represents a bond or (C ₁ -C ₄ ) -alkylene, and R ^{13 represents} Represents a 5- to 9-membered nitrogen heterocyclic ring, which is connected via a ring carbon atom, wherein the 5- to 9-membered nitrogen heterocyclic ring can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and benzyl selected from the group consisting of substituents, and 5- to 9-membered nitrogen heterocycles may be fused with a phenyl ring , Phenyl ring Body may be 1 or 2 of halo, (C ₁ -C ₄₎ - alkyl, (C ₁ -C ₄₎ - group consisting of alkoxy and trifluoromethyl substituent selected from the substituent group, or on behalf of the Department of Adamantyl, R ⁴ represents hydrogen, R ⁵ represents hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₆ ) -cycloalkyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -Alkoxy, amine, 4- to 7-membered heterocyclic or 5- or 6-membered heteroaryl, R ⁶ represents hydrogen, cyano or halogen, and its N-oxides, salts, solvates , N-oxide salts and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆₎ - cycloalkyl, or phenyl, wherein (C ₄ -C ₆₎ - alkyl which may be substituted by fluorine High 6, wherein (C ₄ -C ₆₎ - cycloalkyl may be substituted with 1 or 2 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and methyl, and the phenyl group thereof may be independently substituted by fluorine, chlorine, cyano, methoxy, and ethoxy through 1 to 4 Group, difluoromethyl group, trifluoromethyl group, (C ₃ -C ₆ ) -cycloalkyl group and methyl group. R ² represents hydrogen, trifluoromethyl group, (C ₁ -C ₃ ) -alkyl or cyclopropyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, methylene or 1-2-ethylene, and L ^1C represents a bond or methylene, where The methyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ is Represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, where (C ₁ -C ₆ ) -Alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl via 1 or 2 Selected from the group consisting of phenoxy and benzyloxy, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with one or two substituents selected from the group consisting of fluorine and chlorine, Wherein (C ₃ -C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and phenyl and 5 -Or 6-membered heteroaryl can be independently selected from fluorine, chlorine, cyano, methyl, vinyl, nitrate via 1 or 2 , Difluoromethoxy, _{trifluoromethoxy, -NH (CO) CH 3,} (C 1 -C 4) - alkoxy and trifluoromethyl group consisting of the substituents selected from substituent group, wherein (C _1- C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ together form a 3- to 6-membered carbocyclic ring Or an oxo, tetrahydrofuranyl, tetrahydropiperanyl, azido, pyrrolidinyl, or piperidinyl ring, wherein the 3- to 6-membered carbocyclic and oxo, tetrahydrofuran, tetrahydropiperanyl , Azulenyl, pyrrolidinyl and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other, and R ⁹ represents (C ₁ -C ₄ ) -alkane Group, cyano or phenyl group, wherein (C ₁ -C ₄ ) -alkyl is independently selected from fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl via 1 to 3 Selected from the group consisting of oxy, 5-membered heteroaryl and benzyloxy, wherein benzyloxy can be substituted with 1 to 3 halogen substituents, of which 5-membered heteroaryl is 5-membered Heteroaryl substitution, in which the 5-membered heteroaryl radical itself can be substituted with (C ₁ -C ₄ ) -alkyl, where benzene The radical is substituted by 1 or 2 substituents selected from the group consisting of cyano, difluoromethoxy, trifluoromethoxy, and (C ₁ -C ₄ ) -alkoxy, which are independent of each other, where (C _1- C ₄ ) -alkoxy is substituted with hydroxy, R ¹⁰ is hydrogen or methyl, R ¹¹ is hydrogen or (C ₁ -C ₃ ) -alkyl, of which (C ₁ -C ₃ ) -alkane The group may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, methoxy, and ethoxy independently. R ¹² represents hydrogen, (C ₁ -C ₄ ) -Alkyl, cyclopropyl, cyclobutyl, phenyl or benzyl, wherein (C ₁ -C ₄ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, (C _1- C ₄ ) -Alkoxy and phenoxy groups selected from the group consisting of substituents, and the phenyl and benzyl groups thereof may be independently composed of 1 to 3 fluorine, chlorine and trifluoromethyl groups The selected substituents in the group are substituted, or R ¹¹ and R ¹² form a nitrogen atom, pyrrolidinyl, piperidinyl, morpholinyl, piperidine together with the nitrogen atom to which they are attached. Group, timorpholinyl or 1,1-dioxotimorpholinyl ring, wherein aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl Can be independently selected from fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl via 1 or 2 , Selected from the group consisting of azepine, pyrrolidinyl, and piperidinyl, and L ² represents a bond, methyl or 1,1-ethylene, and R ¹³ represents pyrrolidinyl , Piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-azabicyclo [3.2.1] Octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-aza Bicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen R ⁵ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, monofluoromethyl, methoxy, ethynyl, or cyclopropyl, R ⁶ represents hydrogen or fluorine, and its N- Oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl Or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, where (C ₄ -C ₆ ) -cycloalkyl can be independently replaced by fluorine or trifluoromethyl via 1 or 2 Selected from the group consisting of methyl and methyl groups, and the phenyl group thereof may be independently selected from fluorine, chlorine, cyclopropyl, methoxy and methyl groups through 1 to 3, and R ² represents trifluoromethyl Selected from the group consisting of methyl, methyl, ethyl or cyclopropyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass through one or two methyl groups. Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents hydrogen, trifluoromethyl, (C _1- C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and trifluoromethyl via 1 or 2 Selected from the group consisting of phenyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, and benzyloxy, wherein phenyl, phenoxy, and benzyloxy may themselves be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine, trifluoromethyl, methyl and The substituents selected from the group consisting of ethyl groups, and their phenyl groups may be independently substituted by fluorine, chlorine, cyano, nitro, difluoromethoxy, trifluoromethoxy, -NH Selected substitutions from the group consisting of (CO) CH ₃ , vinyl, ethoxy and trifluoromethyl Group substitution, in which the ethoxy group may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ are carbon atoms connected to them to form a 3- to 6-membered carbocyclic ring or oxygen Fluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, nitrogen The fluorenyl, pyrrolidinyl, and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents ethyl, propyl, cyano, or phenyl. In which, ethyl and propyl are substituted by 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl and benzyloxy, wherein benzyloxy may be substituted by 1 to 3 halogen Substitution, where phenyl is substituted with cyano, difluoromethoxy, trifluoromethoxy, or ethoxy, where ethoxy is substituted with hydroxyl, R ¹⁰ is hydrogen or methyl, and R ¹¹ is hydrogen Or (C ₁ -C ₃ ) -alkyl, in which (C ₁ -C ₃ ) -alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and trifluoromethyl independently of each other, R ¹² represents hydrogen, (C _1- C ₄ ) -alkyl, cyclopropyl or cyclobutyl, wherein (C ₁ -C ₄ ) -alkyl can be selected from 1 or 2 groups independently of each other consisting of fluorine and trifluoromethyl Substituents are substituted, or R ¹¹ and R ¹² form a nitrogen atom, pyrrolidinyl, piperidinyl, or morpholinyl ring together with the nitrogen atom to which they are attached. Among them, the nitrogen atom, pyrrolidyl, piperidinyl and Morpholine may be substituted by 1 or 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl, and L ² represents one Bond or methyl extension, R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indolinyl , 8-azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and linked via a ring carbon atom Of Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 8-azabicyclo [3.2. 1] octyl, 9-azabicyclo- [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen , R ⁵ represents hydrogen, fluorine, chlorine, methyl, ethyl, monofluoromethyl, methoxy, ethynyl, or cyclopropyl, R ⁶ represents hydrogen, and its N-oxides, salts, and solvents Compounds, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula Where # represents the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent hydrogen, fluorine, methoxy, cyclopropyl or chlorine, and the restriction is at least two R ¹⁴ , R ¹⁵ The R ¹⁶ group is not hydrogen, R ² represents a methyl group, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, ( C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and the phenyl group may be independently substituted by fluorine, difluoromethoxy, trifluoromethoxy through 1 or 2 , Vinyl, ethoxy and chlorine selected from the group consisting of substituents, in which ethoxy may be substituted by hydroxyl, R ⁸ represents hydrogen, methyl or ethyl, R ⁹ represents ethyl, cyano or Phenyl, in which ethyl is substituted with fluorine up to 5 times, in which phenyl is substituted with cyano, difluoromethoxy, trifluoromethoxy or ethoxy, where ethoxy is substituted with hydroxyl, R ¹⁰ Represents hydrogen or methyl, R ¹¹ represents hydrogen, R ¹² represents hydrogen, and L ² represents a bond, and R ¹³ represents piperidin-2-yl, piperidin-3-yl, piperidin-4- Or 1,2,3,4-tetrahydroquinolin-4-yl, among which piperidin-2-yl, piperidine-3 -Yl and piperidin-4-yl may be substituted with 1 to 5 substituents selected from the group consisting of trifluoromethyl and methyl independently of each other, and 1,2,3,4-tetrahydroquinoline The -4- group may be substituted by fluorine or trifluoromethyl, R ⁴ represents hydrogen, R ⁵ represents hydrogen, fluorine, chlorine, monofluoromethyl, methoxy, ethynyl or methyl, and R ⁶ represents hydrogen , And its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, wherein (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be substituted by 1 to 4 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, and (C ₁ -C ₄ ) -alkyl, and the phenyl group thereof may be independently replaced by halogen, cyano, Monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, (C ₃ -C ₆ ) -cycloalkyl, A substituent selected from the group consisting of difluoromethoxy and trifluoromethoxy, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl Or trifluoromethyl, R ³ represents a group of the formula Where * represents the point of attachment to the carbonyl group L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene can be independent of each other via 1 to 3 Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, and L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, cyano, 5- to 10-membered heteroaryl, naphthyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from 1 to 3 Fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxy-carbonyl, (C ₁ -C ₄₎ - alkyl sulfo group consisting of acyl, phenyl, phenoxy and benzyloxy substituents selected from the substituent group, wherein the phenyl, benzyl And benzyloxy groups may themselves to 3 halogen or (C ₁ -C ₄₎ via 1-- substituted alkoxy substituent, wherein (C ₃ -C ₇₎ - cycloalkyl may be substituted with 1 or 2 substituents independently of one another Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy, and phenyl and 5- to 10- Heteroaryl groups can be independently selected from halogen, cyano, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -NH (CO) CH _{3, (C 1 -C 4)} - alkyl, (C ₁ -C ₄₎ - cycloalkyl, (C ₁ -C ₄₎ - alkenyl, (C ₁ -C ₄₎ - alkylsulfonyl group, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxy are selected from the group consisting of substituents, in which (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group , And its phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms, R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl, or R ⁷ and R ⁸ The carbon atoms linked to it form a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring and the 4- to 7-membered heterocyclic ring can pass through 1 or 2 substituents independently of one another by fluorine and (C ₁ -C ₄₎ - alkyl group consisting of The selected substituents, R ⁹ represents hydrogen system, cyano, (C ₁ -C ₆₎ - alkyl, (C ₂ -C ₆₎ - alkenyl, (C ₂ -C ₆₎ - alkynyl, (C ₃ -C ₇ ) -cycloalkyl, 5- to 10-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and difluoromethyl via 1 to 3 , Trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, cyano, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl, (C _1- C ₄ ) -alkylsulfonyl, 5- or 6-membered heteroaryl, phenyl, phenoxy and benzyloxy selected from the group consisting of phenyl, phenoxy and Benzyloxy itself can be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, where 5- or 6-membered heteroaryl can be benzo-fused or substituted with 5- or 6- Heteroaryl substitution, where 5- or 6-membered heteroaryl may be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C ₃ -C ₇ ) -cycloalkyl may be substituted with 1 Or two substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy, and phenyl groups thereof And 5- to 10-membered heteroaryl groups can be independently , Difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄₎ - alkyl, (C ₁ -C ₄₎ - cycloalkyl, (C ₁ - A substituent selected from the group consisting of C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl, wherein (C ₁ -C ₄ ) -Alkoxy may be substituted by a hydroxyl group, and the phenyl group may be bridged by a difluoromethylene dioxy group on two adjacent carbon atoms, and R ¹⁰ represents hydrogen or (C ₁ -C ₄ ) -alkane Or R ⁹ and R ¹⁰ are a carbon atom to which they are attached to form a 3- to 7-membered carbocyclic ring or a 4- to 7-membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring and 4- to The 7-membered heterocycle itself may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and (C ₁ -C ₄ ) -alkyl independently of each other, and the restrictions are R ⁷ and R ⁹ Group cannot represent phenyl at the same time, and R ⁷ and R ⁹ are a carbon atom and L ^1B group bonded to form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring, wherein the 3- to The 7-membered carbocyclic ring may be substituted with 1 or 2 substituents selected from the group consisting of (C ₁ -C ₄ ) -alkyl, fluorine, hydroxyl, and (C ₁ -C ₄ ) -alkoxy groups independently of each other. , With restrictions for each R ⁷ and R ^8, R ⁹ and R ¹⁰ and R ⁷ and R ⁹ can not have a group of one or more pairs of carbon formed simultaneously - or heterocyclyl, R ¹¹ are representatives of (C ₁ -C ₄₎ - alkyl, wherein the ( C ₁ -C ₄ ) -alkyl is substituted with 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy, each independently, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, in which (C ₁ -C ₆ ) -alkyl can pass through 1 to 3 Each independently selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and the phenyl and benzyl groups thereof may be substituted by 1 to Three substituents consisting of halogen and trifluoromethyl are substituted independently, or R ¹¹ and R ¹² are nitrogen atoms bonded to them to form a 4- to 7-membered nitrogen heterocycle, wherein the 4- to 7 -Member nitrogen heterocyclic ring system is substituted by 1 or 2 substituents selected from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and 4- to 7-membered heterocyclic ring, and L ² represents A bond or (C ₁ -C ₄ ) -alkylene, R ¹³ represents a 5- to 9-membered nitrogen heterocyclic ring, which is connected via a ring carbon atom, of which 5- to 9-membered nitrogen heterocyclic ring Can be selected from 1 to 5 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and benzyl Substitution, and the 5- to 9-membered nitrogen heterocyclic ring may be fused with a phenyl ring, and the phenyl ring itself may be substituted by one or two halogens, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ )-selected from the group consisting of alkoxy and trifluoromethyl, or represents adamantyl, R ⁴ represents hydrogen, R ⁵ represents hydrogen, halogen, cyano, monofluoromethyl, Difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₆ ) -Cycloalkyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amine, 4- to 7-membered heterocyclic or 5- or 6-membered heteroaryl R ⁶ represents hydrogen, cyano or halogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆₎ - cycloalkyl, or phenyl, wherein (C ₄ -C ₆₎ - alkyl which may be substituted by fluorine High 6, wherein (C ₄ -C ₆₎ - cycloalkyl may be substituted with 1 or 2 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and methyl, and the phenyl group thereof may be independently substituted by fluorine, chlorine, cyano, methoxy, and ethoxy through 1 to 4 Group, substituted with a substituent selected from the group consisting of difluoromethyl, trifluoromethyl, (C ₃ -C ₆ ) -cycloalkyl and methyl, R ² represents hydrogen, trifluoromethyl, (C ₁ -C ₃ ) -alkyl and cyclopropyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, methyl or 1,2-ethylene, and L ^1C represents a bond or methyl, where The methyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ is Represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -Alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl via 1 or 2 Selected from the group consisting of phenoxy and benzyloxy, wherein phenyl, phenoxy and benzyloxy may themselves be substituted with one or two substituents selected from the group consisting of fluorine and chlorine, Wherein (C ₃ -C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and phenyl and 5 -Or 6-membered heteroaryl can be independently selected from fluorine, chlorine, cyano, nitro, methyl, ethylene via 1 or 2 , Difluoromethoxy, _{trifluoromethoxy, -NH (CO) CH 3,} (C 1 -C 4) - alkoxy and trifluoromethyl group consisting of the substituents selected from substituent group, wherein (C _1- C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ together form a 3- to 6-membered carbocyclic ring Or an oxo, tetrahydrofuranyl, tetrahydropiperanyl, azido, pyrrolidinyl, or piperidinyl ring, wherein the 3- to 6-membered carbocyclic and oxo, tetrahydrofuran, tetrahydropiperanyl , Azido, pyrrolidinyl and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents hydrogen, cyano, 1,1, 2,2-tetrafluoroethyl, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, Where (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄₎ - the group consisting of alkoxy, 5-membered heteroaryl, phenyl, phenoxy and benzyloxy substituents selected from the substituent group, wherein the phenyl, phenoxy and benzyl May themselves be substituted with 1 or 2 substituents from the group consisting of fluorine and chlorine substituents selected from the substituent group, wherein the 5-membered heteroaryl groups may be benzo-fused 5-membered heteroaryl or with a substituted aryl group, wherein (C ₃ - C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, and phenyl and 5- or 6-membered Heteroaryl groups can be independently selected from fluorine, chlorine, cyano, methyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy and trifluoromethyl via 1 or 2 Selected from the group consisting of substituents, in which (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ are linked to it Carbon atoms together form a 3- to 6-membered carbocyclic ring or oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azetino, pyrrolidinyl or piperidinyl ring, wherein the 3- to 6-membered carbon ring Rings and oxalyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, and piperidinyl rings can be selected from one or two groups consisting of fluorine, benzyl, and methyl, independently of each other the substituents, with the proviso that both R ⁷ and R ⁹ groups Simultaneously represent methyl, or R ⁷ and R ⁹ Lines and coupling to carbon atoms, and L ^1B groups together form a cyclopentyl group, a cyclohexyl group, a nitrogen Ta group, an oxygen Da group, pyrrolidinyl, tetrahydrofuranyl, piperidinyl Or tetrahydropiperidinyl ring, the restriction is that the respective R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot have more than one pair at the same time represent one of the above carbon- or heterocyclic rings , L ² represents a bond, methyl or 1,1-ethylene, and R ¹¹ represents methyl and ethyl, wherein methyl and ethyl are independently composed of fluorine and trifluoride through 1 to 3 Selected from the group consisting of methyl, hydroxyl and methoxy, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl or Benzyl, where (C ₁ -C ₄ ) -alkyl may be independently composed of fluoro, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy via 1 to 3 Substituents selected from the group, and phenyl and benzyl groups thereof may be substituted with 1 to 3 substituents selected from the group consisting of halogen and trifluoromethyl independently, or R ¹¹ and R ¹² are related to each other. Bonded nitrogen atoms together form a 4- to 6-membered aza Wherein the 4- to 6-membered nitrogen heterocycle may be substituted with 1 or 2 substituents independently of one another by (C ₃ -C ₆₎ - cycloalkyl group and 4- to 6-membered heterocycle selected from the substituent group of Substitution, R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indolyl, Azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl, and those linked via ring carbon Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indololinyl, 8-aza Bicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen R ⁵ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, monofluoromethyl, methoxy, ethynyl, or cyclopropyl, R ⁶ represents hydrogen or fluorine, and its N- Oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl Or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, where (C ₄ -C ₆ ) -cycloalkyl can be independently replaced by fluorine or trifluoromethyl via 1 or 2 And substituents selected from the group consisting of methyl and methyl, and the phenyl group thereof may be selected from 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyclopropyl, methoxy and methyl Substitution, R ² represents trifluoromethyl, methyl, ethyl and cyclopropyl, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass 1 or 2 Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents hydrogen, trifluoromethyl, (C _1- C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and trifluoromethyl via 1 or 2 Selected from the group consisting of phenyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, and benzyloxy, wherein phenyl, phenoxy, and benzyloxy may themselves be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine, trifluoromethyl, methyl and The substituents selected from the group consisting of ethyl groups and their phenyl groups may be independently substituted by fluorine, chlorine, cyano, nitro, vinyl, difluoromethoxy, trifluoromethoxy through 1 or 2 , -NH (CO) CH ₃ , selected substitution in the group consisting of ethoxy and trifluoromethyl Group substitution, in which the ethoxy group may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ are carbon atoms connected to them to form a 3- to 6-membered carbocyclic ring or oxygen Fluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic ring and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, nitrogen The fluorenyl, pyrrolidinyl, and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents hydrogen, cyano, trifluoromethyl, ( C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano and fluorine via 1 or 2 , Trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy and benzyloxy selected from the group consisting of phenyl, phenoxy and benzyloxy The basic body can be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl can be independently substituted by fluorine or trifluoromethyl through 1 or 2 Selected from the group consisting of methyl, methyl and ethyl, and its benzene Can be substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, difluoromethoxy, trifluoromethoxy, ethoxy and trifluoromethyl independently of each other The group may be substituted by a hydroxyl group, and R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbocyclic ring or oxo group, tetrahydrofuran group, Tetrahydropiperanyl, azino, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl And the piperidinyl ring may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and methyl independently of each other, with the limitation that the R ⁷ and R ⁹ groups cannot simultaneously represent phenyl, or R ⁷ and R ⁹ together form a cyclopentyl, cyclohexyl, aziridinyl, oxenyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropiperidinyl ring together with the carbon atom and L ^1B group to which they are attached, with the proviso that respective R ⁷ and R ^8, R ⁹ and R ¹⁰ and R ⁷ and R ⁹ can not have a group of more than one pair of the carbon formed simultaneously - one or heterocycle, R ¹¹ represents a methyl-based Or ethyl, where methyl and ethyl lines selected by one to three groups independently of one another by fluorine, trifluoromethyl, hydroxy and methoxy group consisting of the substituents in, R ¹² represents hydrogen system, (C _1- C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl or benzyl, wherein (C ₁ -C ₄ ) -alkyl can be independently selected from fluorine, Trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and phenoxy groups selected from the group consisting of substituents, and the phenyl and benzyl groups thereof may be independently replaced by halogens through 1 to 3 And selected from the group consisting of trifluoromethyl, or R ¹¹ and R ¹² are nitrogen atoms bonded to them to form a 4- to 6-membered nitrogen heterocyclic ring, wherein the 4- to 6-membered nitrogen The heterocyclic ring may be substituted with 1 or 2 substituents selected from the group consisting of (C ₃ -C ₆ ) -cycloalkyl and 4- to 6-membered heterocyclic ring, and L ² represents a bond or R ¹³ is methyl, R ¹³ represents pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, indolinyl, 8-azabicyclo [3.2.1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and linked via a ring carbon atom Pyridyl, of which pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 8-azabicyclo [3.2. 1] octyl, 9-azabicyclo [3.3.1] nonyl, 3-azabicyclo [4.1.0] heptyl and A pyridyl group may be substituted with 1 to 5 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, and benzyl, and R ⁴ represents hydrogen , R ⁵ represents hydrogen, fluorine, chlorine, methyl, ethyl, monofluoromethyl, methoxy, ethynyl, or cyclopropyl, R ⁶ represents hydrogen, and its N-oxides, salts, and solvents Compounds, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula

Where # represents the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent hydrogen, fluorine, methoxy, cyclopropyl or chlorine, and the restriction is that at least two of them R ¹⁴ , R ¹⁵ , R ^{16 is} not hydrogen, R ² represents a methyl group, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, ( C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and the phenyl group can be independently substituted by fluorine, vinyl, difluoromethoxy, trifluoro through 1 or 2 A substituent selected from the group consisting of methoxy, ethoxy and chlorine, wherein ethoxy may be substituted by hydroxyl, R ⁸ represents hydrogen, methyl or ethyl, R ⁹ represents hydrogen, cyano, tris Fluoromethyl, (C ₁ -C ₆ ) -alkyl, cyclopropyl or phenyl, where (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoro via 1 or 2 Methyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and phenyl groups selected from the substituents, and the phenyl group may be independently substituted by fluorine or difluoromethoxy through 1 or 2 , Trifluoromethoxy, ethoxy and chlorine selected from the group consisting of May be substituted with a hydroxyl group, a carbon-based R ¹⁰ represents hydrogen atom, methyl or ethyl, or R ⁹ and R ¹⁰ lines connected thereto together form a 3- to 6-membered carbocyclic ring or Ta oxide, which The limiting condition is that R ⁷ and R ⁹ groups cannot represent phenyl groups at the same time, and R ¹¹ represents methyl or ethyl, wherein methyl and ethyl are independently selected from fluorine, trifluoromethyl, hydroxyl and Substituted by a substituent selected from the group consisting of methoxy groups, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl or benzyl, where ( C ₁ -C ₄ ) -alkyl may be substituted by 1 to 3 selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, independently of each other. Group substitution, and phenyl and benzyl groups thereof may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen and trifluoromethyl, or R ¹¹ and R ¹² are common to the nitrogen atom to which they are attached Forms a 4- to 6-membered nitrogen heterocyclic ring, wherein the 4- to 6-membered nitrogen heterocyclic ring can be independently from each other by (C ₃ -C ₆ ) -cycloalkyl and 4- to 6- membered heterocyclyl group selected from the composition of the substituents, and L ² represents a bond system, R ¹³ lines Epipiperidin-2-yl, piperidin-3-yl, piperidin-4-yl or 1,2,3,4-tetrahydroquinolin-4-yl, of which piperidin-2-yl, piperidin- 3-yl and piperidin-4-yl can be substituted with 1 to 5 substituents selected from the group consisting of trifluoromethyl and methyl independently of each other, and 1,2,3,4-tetrahydroquine Phenolin-4-yl may be substituted by fluorine or trifluoromethyl, R ⁴ represents hydrogen, R ⁵ represents hydrogen, fluorine, chlorine, monofluoromethyl, methoxy, ethynyl or methyl, and R ⁶ represents Hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, wherein (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, of which (C ₃ -C ₇ ) -cycloalkyl can be substituted by 1 to 4 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, and (C ₁ -C ₄ ) -alkyl, and the phenyl group thereof may be independently replaced by halogen, cyano, Monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, (C ₃ -C ₆ ) -cycloalkyl, A substituent selected from the group consisting of difluoromethoxy and trifluoromethoxy, R ² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, monofluoromethyl, difluoromethyl Or trifluoromethyl, R ³ represents a group of the formula

Where * represents the point of attachment to the carbonyl group L ^1A represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -alkylene can be independent of each other via 1 to 3 Selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy L ^1B represents a bond or (C ₁ -C ₄ ) -alkylene, and L ^1C represents a bond or (C ₁ -C ₄ ) -alkylene, where (C ₁ -C ₄ ) -Alkylene can be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, hydroxyl and (C _1- C ₄ ) -alkoxy group selected substituents, R ⁷ represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, cyano, 5- to 10-membered heteroaryl, naphthyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl Can be independently from 1 to 3 by fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) - alkoxy - carbonyl group, (C ₁ -C ₄₎ - group selected group consisting of alkylsulfonyl, phenyl, phenoxy and benzyloxy The substituents, wherein phenyl, phenoxy and benzyloxy may be itself or 3 halogen (C ₁ -C ₄₎ with 1 to - substituted alkoxy substituent, wherein (C ₃ -C ₇₎ - cycloalkyl The alkyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, and (C ₁ -C ₄ ) -alkoxy, independently of each other. , And its phenyl and 5- to 10-membered heteroaryl groups can be independently selected from halogen, cyano, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy, Fluoromethoxy, -NH (CO) CH ₃ , (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkyl, (C ₁ -C ₄ ) -alkenyl, (C ₁ -C ₄ ) -alkylsulfonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, and (C ₁ -C ₄ ) -alkoxy, selected from the group consisting of (C _1- C ₄ ) -alkoxy may be substituted by a hydroxy group, and two adjacent carbon atoms of the phenyl group may be substituted by a difluoromethylene dioxy bridge. R ⁸ represents hydrogen or (C ₁ -C ₄ )- Alkyl, or R ⁷ and R ⁸ are carbon atoms to which they are attached to form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring, wherein the 3- to 7-membered carbocyclic ring and 4- The 7-membered heterocycle itself may be modified by 1 or 2 by fluorine and (C ₁ -C ₄ ) -Alkyl group selected substituents, R ⁹ represents hydrogen, cyano, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, 5- to 10-membered heteroaryl or phenyl, wherein (C ₁ -C ₆ ) -alkyl may be independent of each other through 1 to 3 Fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, cyano, (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -Alkoxycarbonyl, (C ₁ -C ₄ ) -alkylsulfonyl, 5- or 6-membered heteroaryl, phenyl, phenoxy and benzyloxy selected from the group consisting of substituents, Wherein phenyl, phenoxy and benzyloxy may themselves be substituted with 1 to 3 halogen or (C ₁ -C ₄ ) -alkoxy substituents, where 5- or 6-membered heteroaryl may be benzo-fused Combined or substituted with 5- or 6-membered heteroaryl, wherein 5- or 6-membered heteroaryl may be substituted with (C ₁ -C ₄ ) -alkyl or trifluoromethyl, where (C ₃ -C ₇ ) -Cycloalkyl can be selected from 1 or 2 groups independently of each other consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl and (C ₁ -C ₄ ) -alkoxy Substituent substitution, and its phenyl and 5- to 10-membered heteroaryl groups may be mutually independent through 1 to 3 Sites made from halogen, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -cycloalkane Selected from the group consisting of (C ₁ -C ₄ ) -alkoxy, (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₄ ) -alkylsulfonyl, Wherein (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, and the phenyl group may be substituted by a difluoromethylenedioxy bridge on two adjacent carbon atoms, and R ¹⁰ represents hydrogen or (C _1- C ₄ ) -alkyl, or R ⁹ and R ¹⁰ together form a 3- to 7-membered carbocyclic or 4- to 7-membered heterocyclic ring with the carbon atom to which they are attached, wherein the 3- to 7- The member carbocyclic ring and the 4- to 7-membered heterocyclic ring itself may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and (C ₁ -C ₄ ) -alkyl independently of each other. Provided that the R ⁷ and R ⁹ groups cannot represent phenyl groups at the same time, or that R ⁷ and R ⁹ are connected to the carbon atom and L ^1B group to form a 3- to 7-membered carbocyclic ring or 4- to 7-membered heterocyclic ring. Ring, in which a 3- to 7-membered carbocyclic ring may be independently composed of (C ₁ -C ₄ ) -alkyl, fluorine, hydroxyl, and (C ₁ -C ₄ ) -alkoxy groups via 1 or 2 Selected substituent substitution With the proviso that respective R ⁷ and R ^8, R ⁹ and R ¹⁰ and R ⁷ and R ⁹ can not have a group of one or more pairs of carbon formed simultaneously - or heterocycle, R ¹¹ represents hydrogen or lines (C ₁ - C ₄ ) -alkyl, wherein (C ₁ -C ₄ ) -alkyl may be independently composed of 1 to 3 fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy Substituted by selected substituents in the group, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, where (C ₁ -C ₆ ) -Alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and Phenyl and benzyl may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen and trifluoromethyl, or R ¹¹ and R ¹² together form a 4- to 4- 7-membered nitrogen heterocyclic ring, wherein the 4- to 7-membered nitrogen heterocyclic ring may be independently selected from fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C _3- C ₇ ) -cycloalkyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and 4- to 7-membered heterocyclic ring selected from the group consisting of substituents, and L ² represents a bond Or (C ₁ -C ₄ ) -alkylene, R ¹³ represents a 5- to 9-membered nitrogen heterocycle, which is connected via a ring carbon atom, wherein the 5- to 9-membered nitrogen heterocycle is 1 to 5 substituents independently selected from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and benzyl, R ⁴ represents hydrogen, R ⁵ represents hydrogen, halogen, cyano, and monofluoromethyl Group, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, (C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₆ ) -cycloalkyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amine, 4- to 7-membered heterocyclic ring or 5- or 6-membered heterocyclic Aryl, R ⁶ represents hydrogen, cyano or halogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , CD ₂ or CH (CH ₃ ), R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆₎ - cycloalkyl, or phenyl, wherein (C ₄ -C ₆₎ - alkyl which may be substituted by fluorine High 6, wherein (C ₄ -C ₆₎ - cycloalkyl may be substituted with 1 or 2 Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl and methyl, and the phenyl group thereof may be independently substituted by fluorine, chlorine, cyano, methoxy, and ethoxy through 1 to 4 Group, difluoromethyl group, trifluoromethyl group, (C ₃ -C ₆ ) -cycloalkyl group and methyl group. R ² represents hydrogen, trifluoromethyl group, (C ₁ -C ₃ ) -alkyl or cyclopropyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, methyl or 1,2-ethylene, and L ^1C represents a bond or methyl, where The methyl group may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl independently. R ⁷ is Represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl, where (C ₁ -C ₆ ) -Alkyl can be independently selected from fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C ₁ -C ₄ ) -alkoxy, phenyl via 1 or 2 , Phenoxy and benzyloxy selected from the group consisting of substituents, wherein phenyl, phenoxy and benzyloxy itself may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and chlorine, Wherein (C ₃ -C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl independently of each other, and phenyl and 5 -Or 6-membered heteroaryl can be independently selected from fluorine, chlorine, cyano, nitro, methyl, ethylene via 1 or 2 Group selected from the group consisting of difluoro, difluoromethoxy, trifluoromethoxy, -NH (CO) CH ₃ , (C ₁ -C ₄ ) -alkoxy and trifluoromethyl, wherein ( C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ⁸ represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ together form a 3- to 6-membered carbon. Ring or oxo, tetrahydrofuranyl, tetrahydropiperanyl, azido, pyrrolidinyl or piperidinyl ring, wherein the 3- to 6-membered carbocyclic ring and oxo, tetrahydrofuranyl, tetrahydropiperan Group, aziridinyl, pyrrolidinyl and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents hydrogen, cyano, 1,1 , 2,2-tetrafluoroethyl, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 5- or 6-membered heteroaryl or phenyl , Where (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl, (C _1- C ₄₎ - group consisting of alkoxy, 5-membered heteroaryl, phenyl, phenoxy and benzyloxy substituents selected from the substituent group, wherein the phenyl, phenoxy and benzyl May themselves be substituted with 1 or 2 substituents from the group consisting of fluorine and chlorine substituents selected from the substituent group, wherein the 5-membered heteroaryl groups may be benzo-fused 5-membered heteroaryl or with a substituted aryl group, wherein (C ₃ - C ₆ ) -cycloalkyl may be substituted by 1 or 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, methyl and ethyl, and phenyl and 5- or 6-membered Heteroaryl groups can be independently selected from fluorine, chlorine, cyano, methyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy and trifluoromethyl via 1 or 2 Selected from the group consisting of substituents, in which (C ₁ -C ₄ ) -alkoxy may be substituted by a hydroxyl group, R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ are linked to it Carbon atoms together form a 3- to 6-membered carbocyclic ring or oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azetino, pyrrolidinyl or piperidinyl ring, wherein the 3- to 6-membered carbon ring The ring and oxo, tetrahydrofuranyl, tetrahydropiperanyl, azido, pyrrolidinyl, and piperidinyl rings can be selected from one or two groups consisting of fluorine, benzyl, and methyl, independently of each other. Substituent substitution, the restriction is that R ⁷ and R ⁹ groups cannot be simultaneously Represents phenyl, or R ⁷ and R ⁹ are a carbon atom and a L ^1B group to which they are attached to form a cyclopentyl, cyclohexyl, azido, oxo, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or tetraphenyl A hydropiperidinyl ring, the limiting condition is that each of the R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot form one or more of the above carbon- or heterocyclic rings at the same time, R ¹¹ represents hydrogen or (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, methoxy and Selected from the group consisting of ethoxy groups, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, cyclobutyl, phenyl or benzyl, where (C ₁ -C ₄ ) -Alkyl may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy, and Among them, phenyl and benzyl may be substituted by 1 to 3 substituents selected independently from the group consisting of fluorine, chlorine and trifluoromethyl, or R ¹¹ and R ^{12 may} form a nitrogen together with the nitrogen atom to which they are attached. Fluorenyl, pyrrolidinyl, piperidinyl, morpholinyl, Group, timorpholinyl or 1,1-dioxotimorpholinyl ring, wherein aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperidinyl Can be independently selected from fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl via 1 or 2 , Substituted by a substituent selected from the group consisting of azido, pyrrolidinyl, and piperidinyl, and L ² represents a bond, methylidene, or 1,1-ethylene, and R ¹³ represents 5- to 6-membered nitrogen heterocycles, which are linked via ring carbon atoms, where 5- to 6-membered nitrogen heterocycles are independently composed of (C ₃ -C ₇ ) -cycloalkyl and benzyl via 1 to 3 R ⁴ represents hydrogen, R ⁵ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, monofluoromethyl, methoxy, ethynyl or ring Propyl, R ⁶ represents hydrogen or fluorine, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ , R ¹ represents (C ₄ -C ₆ ) -alkyl, (C ₄ -C ₆ ) -cycloalkyl Or phenyl, where (C ₄ -C ₆ ) -alkyl can be substituted up to 6 times with fluorine, where (C ₄ -C ₆ ) -cycloalkyl can be independently replaced by fluorine or trifluoromethyl via 1 or 2 And substituents selected from the group consisting of methyl and methyl, and the phenyl group thereof may be selected from 1 to 3 substituents independently selected from the group consisting of fluorine, chlorine, cyclopropyl, methoxy and methyl Substitution, R ² represents a trifluoromethyl, methyl, ethyl or cyclopropyl group, and R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass through one or two methyl groups. Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl and cyclobutyl, R ⁷ represents hydrogen, trifluoromethyl, (C _1- C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine and trifluoromethyl via 1 or 2 Selected from the group consisting of phenyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy, and benzyloxy, wherein phenyl, phenoxy, and benzyloxy may themselves be substituted by 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine, trifluoromethyl, methyl and The substituents selected from the group consisting of ethyl groups and their phenyl groups may be independently substituted by fluorine, chlorine, cyano, nitro, vinyl, difluoromethoxy, trifluoromethoxy through 1 or 2 , the group consisting of CH _3, ethoxy and trifluoromethyl -NH (CO) selected from the substituent Substituted, hydroxyl group which may be substituted with ethoxy, R ⁸ carbon atoms system represents hydrogen, methyl or ethyl, or R ⁷ and R ⁸ lines connected thereto together form a 3- to 6-membered carbocyclic or oxygen Ta Group, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl, or piperidinyl ring, wherein the 3- to 6-membered carbocyclic ring and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, azepine Group, pyrrolidinyl and piperidinyl rings may be substituted by 1 or 2 substituents selected from the group consisting of fluorine and methyl independently of each other. R ⁹ represents hydrogen, cyano, trifluoromethyl, (C _1- C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, Selected from the group consisting of trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, phenyl, phenoxy and benzyloxy, wherein phenyl, phenoxy and benzyloxy are It may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and chlorine, wherein (C ₃ -C ₆ ) -cycloalkyl may be independently substituted by fluorine, trifluoromethyl, Selected substituents in groups consisting of methyl and ethyl, and their phenyl groups Can be substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, difluoromethoxy, trifluoromethoxy, ethoxy and trifluoromethyl independently of each other The group may be substituted by a hydroxyl group, and R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbocyclic ring or oxo group, tetrahydrofuran group, Tetrahydropiperanyl, azino, pyrrolidinyl, or piperidinyl rings, wherein the 3- to 6-membered carbocyclic and oxofluorenyl, tetrahydrofuranyl, tetrahydropiperanyl, aziridinyl, pyrrolidinyl And the piperidinyl ring may be substituted by 1 or 2 substituents selected from the group consisting of fluorine, benzyl and methyl independently of each other, with the limitation that the R ⁷ and R ⁹ groups cannot simultaneously represent phenyl, or R ⁷ and R ⁹ together form a cyclopentyl, cyclohexyl, aziridinyl, oxenyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or tetrahydropiperidinyl ring together with the carbon atom and L ^1B group to which they are attached, The restriction is that each of the R ⁷ and R ⁸ , R ⁹ and R ¹⁰ and R ⁷ and R ⁹ groups cannot form one or more of the above carbon- or heterocyclic rings simultaneously. R ¹¹ represents hydrogen or (C ₁ -C ₃ ) -alkyl, wherein (C ₁ -C ₃ ) -alkyl may be substituted with 1 or 2 substituents selected from the group consisting of fluorine and trifluoromethyl independently of each other, R ¹² Represents hydrogen, (C ₁ -C ₄ ) -alkyl, cyclopropyl, or cyclobutyl, where (C ₁ -C ₄ ) -alkyl can be independently selected from fluorine and trifluoromethyl via 1 or 2 The selected group in the composition group is substituted, or R ¹¹ and R ¹² form a nitrogen atom, pyrrolidyl, piperidinyl, or morpholinyl ring together with the nitrogen atom to which they are attached, in which the nitrogen atom, pyrrolidine Group, piperidinyl and morpholinyl rings may be substituted with 1 or 2 substituents selected from the group consisting of fluorine, trifluoromethyl, methyl, ethyl, cyclopropyl, and cyclobutyl independently , And L ² represents a bond or a methyl group, and R ¹³ represents a 5- to 6-membered nitrogen heterocyclic ring, which is connected via a ring carbon atom, wherein the 5- to 6-membered nitrogen heterocyclic ring is connected through 1 to Three substituents independently selected from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and benzyl, R ⁴ represents hydrogen, R ⁵ represents hydrogen, fluorine, chlorine, methyl, ethyl group, monofluoromethyl, methoxy, ethynyl or cyclopropyl, R ⁶ represents hydrogen system, Their N- oxides, salts, solvates, N- oxides and the salts of N- oxides and salts solvates thereof.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula

Where # is the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ are independently of each other hydrogen, fluorine, methoxy, cyclopropyl or chlorine, and the restriction is that at least two of them R ¹⁴ , R ¹⁵ , R ¹⁶ group is not hydrogen, R ² represents methyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -Alkyl, (C ₃ -C ₆ ) -cycloalkyl or phenyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, ( C ₁ -C ₄ ) -alkoxy and phenyl are selected from the group consisting of substituents, and the phenyl group can be independently substituted by fluorine, vinyl, difluoromethoxy, trifluoro through 1 or 2 A substituent selected from the group consisting of methoxy, ethoxy and chlorine, wherein ethoxy may be substituted by hydroxyl, R ⁸ represents hydrogen, methyl or ethyl, R ⁹ represents hydrogen, cyano, tris Fluoromethyl, (C ₁ -C ₆ ) -alkyl, cyclopropyl, or phenyl, where (C ₁ -C ₆ ) -alkyl can be independently selected from cyano, fluorine, and trifluoro via 1 or 2 Methyl, hydroxy, (C ₁ -C ₄ ) -alkoxy and phenyl groups selected from the substituents, and the phenyl group may be independently substituted by fluorine or difluoromethoxy through 1 or 2 , Trifluoromethoxy, ethoxy and chlorine selected from the group consisting of The oxy group may be substituted by a hydroxy group. R ¹⁰ represents hydrogen, methyl or ethyl, or R ⁹ and R ¹⁰ form a 3- to 6-membered carbocyclic ring or oxyfluorenyl ring together. Provided that the R ⁷ and R ⁹ groups cannot represent phenyl groups at the same time, R ¹¹ represents hydrogen, R ¹² represents hydrogen, and L ² represents a bond, and R ¹³ represents a 5- to 6-membered nitrogen heterocyclic ring. Linked via ring carbon atoms, where 5- to 6-membered nitrogen heterocyclic ring systems are substituted with 1 to 3 substituents selected independently from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and benzyl R ⁴ represents hydrogen, R ⁵ represents hydrogen, fluorine, chlorine, monofluoromethyl, methoxy, ethynyl, or methyl, and R ⁶ represents hydrogen, and its N-oxides, salts, and solvates , N-oxide salts and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), wherein A represents CH ₂ , R ¹ represents phenyl, wherein phenyl is substituted with 2 to 3 fluorines, and R ² represents methyl. R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, R ⁸ represents hydrogen, and R ⁹ represents hydrogen or (C ₁ -C ₄ ) -alkyl, R ¹⁰ represents methyl or ethyl, R ¹¹ represents hydrogen, R ¹² represents hydrogen, R ⁴ represents hydrogen, R ⁵ represents hydrogen or methyl, and R ⁶ Represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula Where # represents the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ represent hydrogen or fluorine independently of each other. The restriction is that at least two of the R ¹⁴ , R ¹⁵ , and R ¹⁶ groups are not hydrogen, R ² represents methyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, R ⁸ represents hydrogen, and R ⁹ represents hydrogen or (C ₁ -C ₄ ) -alkyl, R ¹⁰ represents methyl or ethyl, R ¹¹ represents hydrogen, R ¹² represents hydrogen, R ⁴ represents hydrogen, R ⁵ represents hydrogen or methyl, and R ⁶ Represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Particularly preferred in the context of the present invention are compounds of formula (I), wherein A represents CH ₂ , R ¹ represents phenyl, wherein phenyl is substituted with 2 to 3 fluorines, and R ² represents methyl, R ³ represents a group of the formula: Where * is the point of connection with the carbonyl group, L ^1A is a bond, L ^1B is a bond, L ^1C is a bond or methyl, R ⁷ is hydrogen, R ⁸ is hydrogen, and R ⁹ Represents (C ₁ -C ₄ ) -alkyl, wherein (C ₁ -C ₄ ) -alkyl is substituted up to 5 times with fluorine, R ¹⁰ represents methyl or ethyl, R ¹¹ represents hydrogen, and R ¹² Represents hydrogen, R ⁴ represents hydrogen, R ⁵ represents hydrogen or methyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and N-oxides And salts of solvates.

Particularly preferred in the context of the present invention are compounds of formula (I), where A represents CH ₂ and R ¹ represents a phenyl group of the formula Where # represents the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ represent hydrogen or fluorine independently of each other. The restriction is that at least two of the R ¹⁴ , R ¹⁵ , and R ¹⁶ groups are not hydrogen, R ² represents methyl, R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, R ⁸ represents hydrogen, and R ⁹ represents (C _1- C ₄ ) -alkyl, in which (C ₁ -C ₄ ) -alkyl is substituted up to 5 times with fluorine, R ¹⁰ represents methyl or ethyl, R ¹¹ represents hydrogen, and R ¹² represents hydrogen, R ⁴ represents hydrogen, R ⁵ represents hydrogen or methyl, R ⁶ represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and N-oxides and salts Solvate.

Particularly preferred are also given the following compounds

And its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Yitejia is given the following compounds And its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

These three compounds are well known from the literature and by those skilled in the art. Known methods to prepare (see Schemes 6-17).

Yitejia is given the following compounds

And its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ¹ represents a phenyl group of the formula Where # represents the connection point with A, and R ¹⁴ , R ¹⁵ and R ¹⁶ independently represent hydrogen, fluorine or chlorine, and the restriction is that at least two of the R ¹⁴ , R ¹⁵ and R ¹⁶ groups are not hydrogen, and Its N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ² represents methyl and its N-oxides, salts, solvates, N-oxide salts and N-oxides and Solvates of salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ³ represents a group of the formula Where * represents the point of connection with the carbonyl group, L ^1A represents a bond, L ^1B represents a bond or a methyl group, and L ^1C represents a bond or a methyl group, where the methyl group can pass through 1 or 2 Independently substituted by a substituent selected from the group consisting of trifluoromethyl, (C ₁ -C ₄ ) -alkyl, cyclopropyl, and cyclobutyl, and N-oxides, salts, solvates, N-oxide salts and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ³ represents a group of the formula Among them, * represents the point connected with the carbonyl group, R ⁸ represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ³ represents a group of the formula Where * represents the point of attachment to the carbonyl group, and R ¹⁰ represents hydrogen or methyl, and its N-oxides, salts, solvates, salts of N-oxides, and N-oxides and salts Of solvates.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ⁵ represents hydrogen, fluorine, chlorine or methyl, and their N-oxides, salts, solvates, N-oxide salts And solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ⁶ represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and N-oxides and Solvates of salts.

Also preferred in the context of the present invention are compounds of formula (I), where R ¹ represents a phenyl group, wherein the phenyl group can be independently selected from halogen, cyano, monofluoromethyl, difluoro through 1 to 3 Selected from the group consisting of methyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, and wherein phenyl is substituted by 1 or 2 by (C ₃ -C ₇ ) -cycloalkyl , (C ₁ -C ₄ ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy selected from the group consisting of substituents, and their N-oxides, salts, Solvates, N-oxide salts and N-oxide and salt solvates.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ¹ represents phenyl, wherein phenyl is independently selected from fluorine, chlorine, cyano, monofluoromethyl, Selected from the group consisting of difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, and the phenyl group is via (C ₃ -C ₆ ) -cycloalkyl, (C _1- C ₂ ) -alkoxy and trifluoromethoxy groups selected from the group consisting of substituents, and their N-oxides, salts, solvates, N-oxide salts and N-oxides And salts of solvates.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ¹ represents phenyl, wherein phenyl is substituted with 1 to 2 fluorines, and phenyl is via cyclopropyl and methoxy Substituents selected from the group consisting of N-oxides, salts, solvates, N-oxide salts, and N-oxide and salt solvates.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ⁵ represents monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₃ -C ₆ ) -cycloalkyl, ( C ₂ -C ₄ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amine, 4- To 7-membered heterocyclic or 5- or 6-membered heteroaryl, and their N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ⁵ represents monofluoromethyl, difluoromethyl, trifluoromethyl, (C ₃ -C ₆ ) -cycloalkyl, ( C ₂ -C ₄ ) -alkynyl, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, 5- to 6-membered heterocycle or 5- or 6-membered heterocycle Aryl, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ⁵ represents monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, (C ₂ -C ₄ ) -alkyne Groups, methoxy groups, morpholino groups, and their N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ⁷ represents (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkynyl, cyano or phenyl, Wherein (C ₁ -C ₆ ) -alkyl is substituted by 1 to 3 groups independently selected from the group consisting of fluorine, trifluoromethyl, difluoromethoxy, trifluoromethoxy and phenoxy Group substitution, where phenoxy group can be substituted by 1 to 3 fluorine, wherein phenyl group is substituted by cyano, nitro, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, -NH (CO) CH _{3 and} (C ₁ -C ₄ ) -alkenyl, selected from the group consisting of (C ₁ -C ₄ ) -alkoxy Substituted by hydroxy, R ⁸ represents hydrogen or (C ₁ -C ₄ ) -alkyl, and its N-oxides, salts, solvates, N-oxide salts and N-oxides and salts. Solvate.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ⁷ represents (C ₁ -C ₄ ) -alkyl, cyano or phenyl, of which (C ₁ -C ₄ ) -alkyl It is substituted by fluorine up to 5 times, and phenyl is substituted by cyano, difluoromethoxy, trifluoromethoxy, ethoxy, -NH (CO) CH ₃ or vinyl, among which ethoxy is Substituted by hydroxy, R ⁸ represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ⁷ represents (C ₁ -C ₄ ) -alkyl, cyano or phenyl, wherein (C ₁ -C ₄ ) -alkyl It is substituted by fluorine up to 5 times, and phenyl is substituted by cyano, difluoromethoxy, trifluoromethoxy, ethoxy, -NH (CO) CH ₃ or vinyl, among which ethoxy is Substituted by hydroxy, R ⁸ represents hydrogen, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ⁹ represents (C ₁ -C ₄ ) -alkyl, cyano or phenyl, of which (C ₁ -C ₄ ) -alkyl It is selected from the group consisting of 1 to 3 independently consisting of fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 5-membered heteroaryl and benzyloxy Substituent substitution, where benzyloxy can be substituted by 1 to 3 halogen substituents, where 5-membered heteroaryl is substituted by 5-membered heteroaryl, and 5-membered heteroaryl can be substituted by (C _1- C ₄ ) -alkyl substitution, in which the phenyl group is independently composed of 1 or 2 groups consisting of cyano, difluoromethoxy, trifluoromethoxy and (C ₁ -C ₄ ) -alkoxy (C ₁ -C ₄ ) -alkoxy is substituted by hydroxy, R ¹⁰ represents hydrogen or methyl, and its N-oxides, salts, solvates, N-oxides Salts and solvates of N-oxides and salts.

Particularly preferred are the following compounds where R ⁹ represents ethyl, propyl, cyano or phenyl, wherein ethyl and propyl are independently composed of fluoro, trifluoromethyl and benzyloxy via 1 to 3 The selected substituents in the group are substituted, wherein benzyloxy may be substituted by 1 to 3 halogen substituents, wherein phenyl is substituted by cyano, difluoromethoxy, trifluoromethoxy or ethoxy, where Ethoxy is substituted by hydroxy, R ¹⁰ represents hydrogen or methyl, and its N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ⁹ represents ethyl, cyano or phenyl, wherein the ethyl is substituted by fluorine up to 5 times, and the phenyl is substituted by cyano, Difluoromethoxy, trifluoromethoxy or ethoxy substitution, in which ethoxy is substituted by hydroxy, R ¹⁰ represents hydrogen or methyl, and its N-oxides, salts, solvates, N- Oxide salts and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ¹¹ represents (C ₁ -C ₄ ) -alkyl, and (C ₁ -C ₄ ) -alkyl is Independently substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxyl and (C ₁ -C ₄ ) -alkoxy, R ¹² represents hydrogen, (C ₁ -C ₆ ) -alkyl (C ₃ -C ₇ ) -cycloalkyl, phenyl or benzyl, wherein (C ₁ -C ₆ ) -alkyl can be independently selected from fluorine, trifluoromethyl, hydroxyl, ( C ₁ -C ₄ ) -Alkoxy and phenoxy groups selected from the group consisting of substituents, and the phenyl and benzyl groups thereof can be independently composed of 1 to 3 groups consisting of halogen and trifluoromethyl Selected from the substituents, or R ¹¹ and R ¹² are linked to the nitrogen atom to which they are attached to form a 4- to 7-membered nitrogen heterocyclic ring, wherein the 4- to 7-membered nitrogen heterocyclic ring is connected by 1 or 2 Independently substituted by a substituent selected from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and 4- to 7-membered heterocyclic ring, and its N-oxide, salt, solvate, N-oxidation Salts of substances and solvates of N-oxides and salts.

Also preferred in the context of the present invention is the administration of a compound of formula (I), where R ¹¹ represents methyl or ethyl, wherein methyl and ethyl are independently from one another by fluorine, trifluoromethyl , Hydroxy and methoxy, R ¹² represents hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl or benzyl selected from the group consisting of substituents Where (C ₁ -C ₄ ) -alkyl can be independently composed of 1 to 3 groups consisting of fluorine, trifluoromethyl, hydroxyl, (C ₁ -C ₄ ) -alkoxy and phenoxy Selected substituents, and the phenyl and benzyl groups thereof may be substituted with 1 to 3 substituents selected from the group consisting of halogen and trifluoromethyl independently, or R ¹¹ and R ¹² are linked to it The nitrogen atoms together form a 4- to 6-membered nitrogen heterocyclic ring, wherein the 4- to 6-membered nitrogen heterocyclic ring can be independently formed by (C ₃ -C ₆ ) -cycloalkyl and 4- Substituents selected from the group consisting of 6-membered heterocyclic rings, and their N-oxides, salts, solvates, salts of N-oxides, and solvates of N-oxides and salts.

Also preferred in the context of the present invention are compounds of formula (I), wherein R ¹³ represents a 5- to 9-membered nitrogen heterocycle, which is linked via a ring carbon atom, of which 5- to 9-membered aza The ring system is substituted with 1 to 5 substituents selected from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and benzyl, and their N-oxides, salts, solvates, N- Oxide salts and solvates of N-oxides and salts.

Also preferred in the context of the present invention is the administration of a compound of formula (I), wherein R ¹³ represents a 5- to 6-membered nitrogen heterocycle, which is linked via a ring carbon atom, wherein 5- to 6-membered aza The ring system is substituted with 1 to 3 substituents selected from the group consisting of (C ₃ -C ₇ ) -cycloalkyl and benzyl, and their N-oxides, salts, solvates, N- Oxide salts and solvates of N-oxides and salts.

In particular, the definitions of the groups referred to in the respective group combinations or preferred combinations may also be arbitrarily substituted with other combinations, regardless of the specific group combination referred to.

Particularly preferred is a combination of two or more of the foregoing preferred ranges.

The present invention further provides a method for preparing the compound of formula (I) of the present invention, characterized in that [A] combines the compound of formula (II) Wherein A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the definitions shown above, and T ¹ represents (C ₁ -C ₄ ) -alkyl or benzyl, and is suitable in an inert solvent. React in the presence of a base or acid to give a carboxylic acid of formula (III) Wherein A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the definitions shown above, and then they are combined with formula (IV-A) or (IV) in an inert solvent under amidine-coupling conditions. -B) an amine reaction, Wherein L ^1A , L ^1B , L ^1C , L ² , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the definitions shown above, and R ^11A , R ^12A and R ^13A have R ¹¹ , R ¹² and R, respectively The definition shown in ¹³ or represents a monoamine protecting group, such as a third butoxycarbonyl group, a benzyloxycarbonyl group or a benzyl group, or [B] a compound of formula (III-B) Wherein R ² , R ⁴ , R ⁵ and R ⁶ each have the definitions shown above, and are reacted with an amine of formula (IV) in an inert solvent under amidine-coupling conditions to obtain formulas (IA) and (IB). Compound Wherein R ² , R ⁴ , R ⁵ , R ⁶ , L ^1A , L ^1B , L ^1C , L ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11A , R ^12A, and R ^13A each have the above shown. And then using methods known to those skilled in the art to remove the benzyl group from this compound and the resulting compound of formula (VA) or (VB) Wherein R ² , R ⁴ , R ⁵ , R ⁶ , L ^1A , L ^1B , L ^1C , L ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11A , R ^12A, and R ^13A each have the above shown. Definition of reacting with a compound of formula (VI) in the presence of a suitable base in an inert solvent Wherein A and R ¹ each have the definition shown above, and X ¹ represents a suitable leaving group, especially chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate or toluenesulfonate, The protective groups present are subsequently removed and the resulting compound of formula (I) is converted into its solvates, salts and / or salts with an appropriate (i) solvent and / or (ii) acid or base as necessary Of solvates.

The compounds of formulae (IA) and (IB) form a subgroup of the compounds of formula (I) according to the invention. The preparation method can be illustrated by the following synthetic schemes (schemes 1 and 2) by way of example: [a): lithium hydroxide, THF / methanol / H ₂ O, RT; b): HATU, N, N-diisopropylethylamine, DMF, RT].

[a): TBTU, N-methylmorpholine, DMF; b): H ₂ , Pd / C, ethyl acetate; c): Cs ₂ CO ₃ , DMF].

Compounds of formulae (IV-A), (IV-B) and (VI) are commercially available, are known from the literature or can be prepared by methods similar to those known in the literature.

The free base of (IV-A) can be obtained from compound (IV-A) (provided as an amine protecting group if necessary), for example, by using an acid such as hydrogen chloride and trifluoroacetic acid in a suitable solvent such as diethyl ether, methylene chloride, 1,4-two Alkane, water, methanol, ethanol and mixtures thereof are released.

The inert solvents used in method steps (III) + (IV) → (I) and (III-B) + (IV) → (IB) are, for example, ethers, such as ether, Alkane, tetrahydrofuran, glycerol dimethyl ether or ethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane Methane, carbon tetrachloride, 1,2 dichloroethane, trichloroethylene, chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethylsulfinium, N, N-dimethylformamide Amidoamine, N, N-dimethylacetamide, N, N'-dimethylpropylene urea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of the above solvents can also be used. Preferably, methylene chloride, tetrahydrofuran, dimethylformamide or a mixture of these solvents is administered.

Suitable condensing agents for the formation of amidines in method steps (III) + (IV) → (I) and (III-B) + (IV) → (IB) are, for example, carbodiimides such as N, N ' -Diethyl-, N, N'-dipropyl-, N, N'-diisopropyl-, N, N'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethyl Aminoaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N, N'-carbonyldiimidazole (CDI), 1,2- Azolium compounds such as 2-ethyl-5-phenyl-1,2- Azolium 3-sulfate or 2-tert-butyl-5-methyliso Azolium perchlorate, fluorenylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline or isobutyl chloroformate, propylphosphonic anhydride (T3P), chlorine -N, N, 2-trimethylpropene-1-amine, diethyl cyanophosphate, bis (2-oxo-3- Amidazinyl) phosphonium chloride, benzotriazol-1-yloxytris (dimethylamino) hexafluorophosphonium or benzotriazol-1-yloxytris (pyrrolidino) hexafluorophosphate Pyrene (PyBOP), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyltetrafluoroborate (TBTU), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethylhexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyltetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylhexafluorophosphate (HATU) or O- (1H-6-chlorobenzotriazol-1-yl) -1,1,3,3-tetramethyltetrafluoroborate (TCTU), if appropriate, in combination with additional adjuvants such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and alkali metal carbonates such as sodium carbonate or potassium carbonate or carbonate Sodium hydrogen or potassium bicarbonate, or organic bases such as trialkylamines, such as triethylamine, N-methylmorpholine, N-methylpiperidine, or N, N-diisopropylethylamine. The preferred system is the combination of TBTU and N-methylmorpholine, HATU and N, N-diisopropylethylamine or 1-chloro-N, N, 2-trimethylprop-1-ene-1 Amine combination.

Condensation (III) + (IV) → (I) and (III-B) + (IV) → (IB) are generally performed in a temperature range from -20 ° C to + 100 ° C, preferably from 0 ° C To + 60 ° C. The reaction can be carried out at atmospheric pressure, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally carried out at atmospheric pressure.

In addition, the carboxylic acid of formula (III) can be initially converted into the corresponding carbonyl chloride and then reacted with the amine of formula (IV) directly or in a separate reaction to obtain the compound of the present invention. The formation of carbonyl chloride from a carboxylic acid is performed by methods known to those skilled in the art, such as by using thionyl chloride, thionyl chloride, or chloramphenicol in the presence of a suitable base, such as the presence of pyridine Then, if necessary, dimethylformamide is added, and if necessary, it is processed in a suitable inert solvent.

The hydrolysis of the ester group T ¹ of the compound of the formula (II) is carried out in a conventional manner by treating the ester with an acid or a base in an inert solvent, in which case the initially formed salt is converted to free by acid treatment. carboxylic acid. In the case of a third butyl ester, the ester cleavage is preferably carried out with an acid. In the case of benzyl esters, ester cleavage is preferably carried out by hydrolysis using palladium or Raney nickel on activated carbon. Suitable inert solvents for this reaction are water or organic solvents customary for ester cleavage. These preferably include alcohols such as alcohols such as methanol, ethanol, n-butanol, isopropanol, n-butanol or tertiary butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, Alkane or glycerol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethylmethylene. Mixtures of the solvents mentioned can also be used. In the case of alkaline ester hydrolysis, it is better to use water and Alkane, tetrahydrofuran, methanol and / or ethanol.

Suitable bases for ester hydrolysis are customary inorganic bases. These preferably include bases Metal or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate or calcium carbonate. Particularly preferably, sodium hydroxide or lithium hydroxide is administered.

Suitable acids for ester hydrolysis are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or The mixture, if appropriate, is added with water. More preferred is the administration of hydrogen chloride or trifluoroacetic acid in the case of the third butyl ester, and hydrochloric acid in the case of the methyl ester.

Ester cracking is generally performed in a temperature range from 0 ° C to + 60 ° C, preferably from 0 ° C to + 50 ° C.

The mentioned reactions can be carried out under atmospheric pressure, elevated or reduced pressure (for example 0.5 to 5 bar). In general, the reaction is carried out under atmospheric pressure in each case.

The inert solvents used in method steps (V) + (VI) → (I) are, for example, halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, trichloroethane or chlorobenzene, ethers, E.g. ether, di Alkane, tetrahydrofuran, glycerol dimethyl ether or ethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or other solvents such as acetone, methyl ethyl Ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylmethylene, N, N'-dimethylpropylene urea (DMPU) , N-methylpyrrolidone (NMP) or pyridine. Mixtures of the solvents mentioned can also be used. Preferably, dimethylformamide or dimethylmethane is used.

Suitable bases for method steps (V) + (VI) → (I) are conventional inorganic or organic bases. These preferably include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, if appropriate, Addition of alkali metal iodides, such as sodium or potassium iodide, alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethoxide, or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride Or potassium hydride, ammonium such as sodium ammonium, lithium bis (trimethylsilyl) amidamine or potassium bis (trimethylsilyl) amidamine or lithium diisopropylammonium, or organic amines such as triethyl Amine, N-methylmorpholine, N-methylpiperidine, 'N, N-diisopropylethylamine, pyridine, 4- (N, N-dimethylamino) pyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4 -Diazabicyclo [2.2.2] octane (DABCO ^® ). Preferably, potassium carbonate, cesium carbonate or sodium methoxide is used.

The reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably from + 20 ° C to + 80 ° C, if appropriate in a microwave. The reaction can be carried out under atmospheric pressure, elevated or reduced pressure (for example 0.5 to 5 bar).

The amine protecting group is preferably a third butoxycarbonyl group (Boc) or a benzyloxycarbonyl group (Z). As the hydroxyl or carboxyl functional group, a third butyl or benzyl group is preferably used as the protecting group. Removal of these protecting groups is performed in a conventional manner, preferably by contacting with a strong acid, such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid, in an inert solvent such as two The reaction is carried out in alkane, ether, dichloromethane or acetic acid; if appropriate, this removal can also be carried out without the addition of any inert solvent. In the case of benzyl or benzyloxycarbonyl as the protecting group, this group is preferably hydrogenolyzed and removed in the presence of a suitable palladium catalyst such as palladium on activated carbon. Removal of the protecting groups can be performed simultaneously in a one-pot reaction or in separate reaction steps.

Here, the removal of the benzyl group in the reaction steps (IB) → (V) is performed by conventional methods known in protection chemistry, preferably by hydrogenolysis, on a suitable palladium catalyst such as active In the presence of palladium on carbon, in an inert solvent, such as ethanol or ethyl acetate [see also, for example, TW Greene and PGMWuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

Compounds of formula (II) are known in the literature or can be obtained by combining compounds of formula (VII) Wherein R ⁴ , R ⁵ and R ⁶ each have the definitions shown above, and are reacted with a compound of formula (IV) in an inert solvent in the presence of a suitable base to obtain a compound of formula (VIII) Wherein R ¹ , R ⁴ , R ⁵ and R ⁶ each have the definition shown above, and then reacted with a compound of formula (IX) in an inert solvent Wherein R ² and T ¹ each have the definition shown above.

The described method is illustrated (flow 3) by way of example through the following flow (flow 3): [a): i) NaOMe, MeOH, RT; ii) DMSO, RT; b): EtOH, molecular sieve, reflux].

The synthesis sequence shown can be modified so that the individual reaction steps are performed in a different order. An example of this modified synthesis sequence is shown in Scheme 4.

[a): EtOH, molecular sieve, reflux; b): b) Cs ₂ CO ₃ , DMF, 50 ° C.].

The inert solvent used for cyclization to obtain the imidazo [1,2-a] pyridine skeleton (VIII) + (IX) → (II) or (VII) + (IX) → (X) is a conventional organic solvent. These preferred systems include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tertiary butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, Alkane or glycerol dimethyl ether, or other solvents such as acetone, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethylformamide, or dimethylmethylene. Mixtures of the solvents can also be used. Preferably, ethanol is used.

The cyclization is usually performed in a temperature range from + 50 ° C to + 150 ° C, preferably from + 50 ° C to + 100 ° C, if appropriate in a microwave oven.

The cyclization (VIII) + (IX) → (II) or (VII) + (IX) → (X) is performed in the presence of a dehydrating agent as needed, for example, in a molecular sieve (pore size 4Å) or using a water separator. The reaction (VIII) + (IX) → (II) or (VII) + (IX) → (X) is performed using an excess of the reagent of formula (IX), for example, using 1 to 20 equivalents of the reagent (IX), if appropriate A base (such as sodium bicarbonate) is added, where the addition of this reagent can be performed once or divided into several times.

In addition, in Schemes 1 to 4, R ^{1 is} introduced by the reaction of compound (V), (VII) or (X) with a compound of formula (VI), as shown in Scheme 5-these intermediates can be combined with formula (XI ) Alcohols are reacted under Mitsunobu reaction conditions.

Typical reaction conditions for the photoelastic reaction of these phenols and alcohols can be found in related literatures, such as Hughes, DLOrg. React. 1992 , 42,335; Dembinski, R. Eur. J. Org. Chem. 2004 , 2763. Typically, compounds are reacted with an activator, such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and a phosphine reagent, such as triphenylphosphine or tributylphosphine. The reaction is carried out in an inert solvent, such as THF, dichloromethane, toluene or DMF, at a temperature between 0 ° C and the boiling point of the solvent used.

Other operating examples can be prepared by methods known in the literature and familiar to those skilled in the art, such as shown in the following schemes 6-17.

Preparation of amines:

Synthesis of operating examples:

Other compounds of the present invention can also be prepared by conversion of individual functional group groups, especially those listed in R ^3, from the compound of formula (I) obtained by the above process, if necessary. These transformations are performed by conventional methods known to those skilled in the art and include, for example, nucleophilic and electrophilic substitution, oxidation, reduction, hydrogenation, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, Esterification, ester cleavage, etherification, ether cleavage, formation of carboxamide, and introduction and removal of temporary protecting groups.

The compounds of the invention have useful pharmacological properties and can be used to prevent and treat disorders in humans and animals. The compounds of the invention open up another therapeutic option and are therefore an improvement in pharmaceuticals.

The compounds of the present invention relax blood vessels and inhibit platelet aggregation, resulting in lowered blood pressure and increased coronary blood flow. These effects are due to the direct stimulation of soluble guanylate cyclase and increased intercellular cGMP. Furthermore, the compounds of the present invention enhance the action of substances that increase the amount of cGMP, such as EDRF (endothelium-derived relaxing factor), NO donors, proviolas IX, arachidonic acid or phenylhydrazine derivatives.

The compounds of the invention are suitable for the treatment and / or prevention of cardiovascular, pulmonary, thromboembolic and fibrotic diseases.

The compounds of the invention are therefore useful in pharmaceutical products for the treatment and / or prevention of cardiovascular diseases such as hypertension, refractory hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina, peripheral and cardiovascular diseases, Arrhythmias, atrial and ventricular rhythm disturbances and conduction disorders, such as I-III degree atrioventricular block (AVB I-III), upper ventricular frequency, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, Ventricular frequency, torsional tachycardia, extraatrial and ventricular systole, pre-ventricular contraction, sick sinus syndrome, atrioventricular reentrant tachycardia, Wolf-Parkinson-White syndrome, acute Coronary Syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvulitis, aortic inflammation, cardiomyopathy), shock such as psychogenic shock, septic shock and anaphylactic shock, aneurysm Boxer myocarditis (early ventricular contraction (PVC)) for the treatment and / or prevention of thromboembolic diseases and ischemia such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attack, pregnancy poisoning Anemia, inflammatory cardiovascular disease, coronary and peripheral arterial spasm, edema, such as pulmonary edema, cerebral edema, renal edema or edema due to heart failure, peripheral perfusion disorders, reperfusion injury, arterial and venous thrombosis, microalbumin Urine, myocardial insufficiency, endothelial dysfunction, used to prevent restenosis such as thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery And microvascular and macrovascular injury (vasculitis), increased amounts of fibrinogen and low-density LDL, increased concentrations of plasminogen activator inhibitor type 1 (PAI-1), and for treatment and / Or prevent erectile dysfunction and female sexual dysfunction.

For the purposes of the present invention, the term heart failure includes manifestations of acute and chronic heart failure, as well as more specific or related forms of disease such as acute decompensated heart failure, right ventricular failure, left ventricular failure, total heart failure, deficiency Bloody cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart disease, heart failure with valvular defects, mitral stenosis, mitral insufficiency, aortic stenosis, aorta Incomplete valve atresia, tricuspid valve stenosis, tricuspid valve occlusion, pulmonary valve stenosis, pulmonary valve occlusion, combined valve occlusion Insufficiency, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, storage-type cardiomyopathy, diastolic heart failure and systolic heart failure, and the acute phase of existing chronic heart failure (Aggravating heart failure).

In addition, the compounds of the present invention can also be used to treat and / or prevent arteriosclerosis, disorders of lipid metabolism, hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hypercholesterolemia, beta lipoproteinemia Disease, sitosterolaemia, xanthomatosis, Tangier disease, excess fat, obesity, and combined hyperlipidemia and metabolic syndrome.

Furthermore, the compounds of the present invention are useful for the treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic limb ulcer, gangrene , CREST syndrome, erythematous disorders, onychomycosis, rheumatism and used to promote wound healing.

In addition, the compounds of the present invention are suitable for the treatment and / or prevention of urological diseases, such as prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hypertrophy (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS, including cat's urological syndrome (FUS)), urinary diseases including neuroactive bladder overactivity (OAB) and (IC), urinary incontinence (UI), such as mixed, urgency, stress or overflow Incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant diseases of the organs of the male and female urinary systems.

In addition, the compounds of the present invention are suitable for the treatment and / or prevention of kidney diseases, especially acute and chronic renal insufficiency, and acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes the characterization of acute and chronic renal insufficiency, as well as underlying or related kidney diseases such as renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, renal filament Globulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, nephropathy diseases such as primary and congenital kidney disease, nephritis, immune kidney disease such as renal transplant rejection , Kidney disease caused by immune complexes, kidney disease caused by toxic substances, nephropathy caused by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, renal sclerosis, Hypertensive nephrosclerosis and renal syndromes may be characterized by, for example, abnormal decrease in serum creatinine and / or water excretion, abnormal increase in blood urea, nitrogen, potassium and / or serum creatinine concentration, renal enzymes such as bran Changes in amino acid synthase activity, changes in urinary osmotic pressure or urine volume, increased microalbumin, macroalbumin, glomerular and arteriolar disease, tubular dilatation, hyperphosphatemia, and / or the need for dialysis. The invention also includes the use of a compound of the invention for the treatment and / or prevention of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalance (e.g. hyperkalemia, hyponatremia), and Disorders of bone and carbohydrate metabolism.

In addition, the compounds of the present invention are also suitable for the treatment and / or prevention of asthma, pulmonary hypertension (PAH), and other forms of pulmonary hypertension (PH), including diseases associated with left ventricle disease, HIV, sickle anemia, and thromboembolism (CTEPH ), Sarcomatoid disease, COPD or pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α-1-antitrypsin deficiency (AATD), lung Fibrosis, emphysema (eg, emphysema caused by smoking), and pulmonary hypertension associated with cystic fibrosis (CF).

The compounds described in the present invention are also effective substances for controlling diseases of the central nervous system characterized by NO / cGMP system disorders. In particular, it applies to cognitive impairments, such as those that occur in specific conditions / diseases / symptoms, such as mild cognitive impairment, aging-related learning and memory disorders, aging-related amnesia, vascular dementia, head injury, stroke , Post-stroke dementia, after traumatic head injury, general attention disorder, attention deficit in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, frontotemporal degeneration dementia Including Pick's disease, Parkinson's disease, progressive nuclear paralysis, dementia with degeneration of the cortical basal nucleus, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelinating, multiple The ability to improve sensation, concentration, learning or memory performance after sclerosis, degeneration of the optic mast, Kujaya's disease, HIV-dementia, dementia schizophrenia or Korsakov psychosis. It is also suitable for the treatment and / or prevention of diseases of the central nervous system, such as anxiety, tension and depression, CNS-related sexual dysfunction and sleep disorders, and control of pathological dietary disorders and use of luxury foods and addictive drugs.

In addition, the compounds of the present invention are also suitable for controlling cerebral perfusion and for combating migraine. Effective medicament. It is also suitable for the prevention and control of sequelae of cerebral infarction (cerebral hemorrhage), such as stroke, cerebral ischemia and head injury. The compounds of the present invention are also useful for controlling pain and tinnitus.

In addition, the compounds of the invention have anti-inflammatory effects and are therefore useful as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, cloning 'S disease, UC), pancreatitis, peritonitis, rheumatoid disease, inflammatory skin disease and inflammatory eye disease.

Furthermore, the compounds of the present invention can also be used to treat and / or prevent autoimmune diseases.

In addition, the compounds of the present invention are suitable for treating and / or preventing visceral fibrotic diseases, such as fibrotic diseases of the lung, heart, kidney, bone marrow, and especially the liver, and fibrotic diseases of the skin and eyes. In the sense of the present invention, the term fibrotic disease system includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endocardial fibrosis, nephropathy, glomerular fibrosis, interstitial renal fibers Fibrosis, diabetes-induced fibrotic lesions, myelofibrosis and similar fibrotic diseases, scleroderma, scleroderma, crabfoot, hypertrophic scars (including after surgery), moles, diabetic retinopathy, proliferative vitreous retina Lesions and connective tissue diseases (such as sarcomatoid disease).

In addition, the compounds of the present invention are suitable for controlling scarring after surgery, such as scarring after glaucoma surgery.

The compounds of the present invention can also be used for aging and keratinizing the skin on beauty makeup.

Furthermore, the compounds of the present invention are suitable for treating and / or preventing hepatitis, tumors, osteoporosis, glaucoma and gastroparesis.

The invention further relates to the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

The invention further relates to the use of a compound of the invention for the treatment and / or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, renal insufficiency, thromboembolic disease, fibrotic disease and arteriosclerosis.

The present invention further relates to a method for treating and / or preventing heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, renal insufficiency, thromboembolic disease, fibrotic disease, and arteriosclerosis. the use of.

The invention further relates to the use of a compound of the invention for the manufacture of a medicinal product for the treatment and / or prevention of diseases, especially the aforementioned diseases.

The invention further relates to the compounds of the invention for use in the manufacture of pharmaceutical products for the treatment and / or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, renal insufficiency, thromboembolic disease, fibrotic disease and arteries Uses for hardening.

The invention further relates to a method for the treatment and / or prevention of diseases, especially the aforementioned diseases, using an effective amount of at least one compound of the invention.

The invention further relates to the use of an effective amount of at least one compound of the invention for the treatment and / or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, renal insufficiency, thromboembolic disease, fibrosis Methods of disease and arteriosclerosis.

The compounds according to the invention can be used alone or in combination with other active substances if necessary. The invention further relates to a medicinal product comprising at least one compound of the invention and one or more other active substances, in particular for the treatment and / or prevention of the aforementioned diseases. Active substances which may be mentioned in suitable combinations are, for example and preferably: ‧ organic nitrates and NO-donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, Molsidomine or SIN-1 and inhaled NO; compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterase (PDE) 1, 2 and / or 5, especially PDE-5 inhibitors, such as sildenafil, vardenafil, and tadalafil; antithrombotic agents, such as and preferably from platelet aggregation inhibitors, anticoagulants Agents or groups of plasminogens; ‧Antihypertensive active substances, such as and preferably derived from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, A group of mineral corticoid receptor antagonists and diuretics; and / or ‧ active substances that alter fat metabolism, such as and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as and preferably HMG- CoA-reductase or squalene synthesis inhibitor, ACAT inhibitor, CETP inhibitor, MTP inhibitor, PPAR-α, PPAR-γ and / or PPAR-δ agonist, cholesterol absorption inhibitor, lipolytic enzyme inhibitor Agents, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

Antithrombotic agents are preferably understood as compounds from the group of platelet aggregation inhibitors, anticoagulants or plasminogen substances.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a platelet aggregation inhibitor, such as and preferably aspirin, clopidogrel, or ticlopidine ( ticlopidine) or dipyridamole.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a thrombotic inhibitor, such as, and preferably, ximelagatran, dabigatran, and melagatran , Bivalirudin or clexane.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a GPIIb / IIIa antagonist, such as and preferably tirofiban or abciximab.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a factor Xa inhibitor, such as, and preferably, rivaroxaban (BAY 59-7939), DU-176b, and axaban (apixaban), otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the present invention, the compound of the present invention is Sub-volume (LMW) heparin derivatives are administered in combination.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vitamin K antagonist, such as and preferably coumarin.

It should be understood that blood pressure is preferably derived from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-blockers, β-blockers, mineral corticoid receptors. Group of body antagonists and diuretics.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil, or Diltiazem.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an α-1-receptor blocker, such as and preferably prazole (prazosin).

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a β-blocker, such as, and preferably, propranolol, atenolol, timolol Timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, mepentrolol ( metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betataxolol ), Celiprolol, bisoprolol, carteolol, esmolol, Labetalol, carvedilol, ada Adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an angiotensin AII antagonist, such as and preferably losartan, candesartan, valsartan ( valsartan), telmisartan or embursatan.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lysinol Lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril, or trondopril (trandopril).

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an endothelin antagonist, such as, and preferably, bosentan, darusentan, ambrisentan Or sitaxsentan.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a renin inhibitor, such as, and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a mineral corticoid receptor antagonist, such as, and preferably, spironolactone or eplerenone.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a cyclic diuretic, such as furosemide, torasemide, bumetanide, pirostatin (piretanide), administered in combination with potassium-sparing diuretics, such as amiloride, triamteren, and aldosterone antagonists, such as spironolactone, potassium cansium (potassium canrenoate) and eplerenone Diuretics in combination, such as hydrochlorothiazide (hydrochlorothiazide), chlorothiazide (chlorothiazide), xipamide, and indapamide.

It should be understood that agents that alter fat metabolism are preferably derived from CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA-reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ, and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipolytic enzyme inhibitors, and lipoprotein (a) antagonists group.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a CETP inhibitor, such as, and preferably, dalcetrapib, BAY 60-55521, anacetrapib or CETP -Vaccine (CETi-1).

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a thyroid receptor agonist, such as and preferably D-thyroxine, 3,5,3'-triiodothyroxine (T3) , CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a HMG-CoA-reductase inhibitor from a statin, for example, and preferably lovastatin, simvastatin , Pravastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an ACAT inhibitor, such as, and preferably, avasimibe, melinamide, pactimibe , Eflucimibe, or smp-797.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with an MTP inhibitor, such as, and preferably, impitalpide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-γ agonist, such as, and preferably, pioglitazone or rosiglitazone.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a PPAR-δ agonist, such as and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a cholesterol absorption inhibitor, such as, and preferably, ezetimibe, tiqueside, or pamaqueside. .

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a lipolytic enzyme inhibitor, such as, and preferably, orlistat.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a polymer bile acid adsorbent, such as and preferably cholestyramine, colestipol, and colesevelam (colesolvam), cholestagel, or colesolv (colestimide).

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a bile acid resorption inhibitor, such as, and preferably, an ASBT (= IBAT) inhibitor, such as AZD-7806, S-8921, AK- 105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a lipoprotein (a) antagonist, such as, and preferably, gemcabene calcium (CI-1027) or nicotinic acid.

The invention further relates to a medicinal product containing at least one compound of the invention, usually together with one or more non-toxic, pharmaceutically suitable excipients, and its use for the aforementioned purposes.

The compounds of the invention may have systemic and / or local effects. It can be administered in a manner suitable for this purpose, such as via oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, dermal, transdermal, conjunctival or intraaural administration or as an implant or support.

The compounds of the invention can be administered in dosage forms suitable for these routes of administration.

Suitable for oral administration is a form of administration for the rapid and / or modified release of a compound of the invention in accordance with prior art dosage forms, which contains a compound of the invention in crystalline and / or amorphous and / or dissolved form, such as Lozenges (uncoated or coated lozenges, such as enteric or delayed-dissolved or insoluble film-coated with controlled release of the compounds of the present invention), lozenges or films / flakes, films that disintegrate rapidly in the mouth / Lyophilisates, capsules (eg hard or soft capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass absorption steps (eg, intravenous, intraarterial, intracardiac, intraspinal, or lumbar) or include absorption (eg, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Dosage forms suitable for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions or lyophilisates or sterile powders.

Suitable other routes of administration are, for example, inhalable pharmaceutical forms (including powder inhalers, sprayers), nasal drops, solutions or sprays, or lozenges for tongue, sublingual or buccal administration, Films / flakes or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (emulsions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), lotions, pastes Agent, foam, dust, implant or stent.

Oral or parenteral administration is preferred, especially oral administration.

The compounds of the present invention can be converted into the aforementioned dosage forms. It can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxygen Sorbitol oleate), binding agents (such as polyvinylpyrrolidone), synthetic and natural polymers (such as albumin), stabilizers (such as antioxidants such as ascorbic acid), colorants (such as inorganic pigments such as oxidation Iron) and taste and / or odor correctors.

In general, in the case of parenteral administration, it has proven advantageous to administer an amount of from about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight. For oral administration, the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg / kg of body weight.

However, it may be necessary to deviate from the stated amount, that is, depending on the body weight, the route of administration, the individual's response to the active compound, the type of preparation and the time point or interval of administration. Therefore, in some cases it is sufficient to be below the above-mentioned minimum amount, in other cases it is necessary to exceed said upper limit. When larger amounts are administered, it is appropriate to divide these amounts into several individual doses dispersed throughout the day.

The following examples illustrate the invention. The invention is not limited to these examples.

Unless otherwise stated, the percentages in the following tests and examples are percentages by weight; parts are parts by weight. In each case, the solvent, dilution ratio and concentration ratio of the liquid / liquid solution refer to the volume.

A. Examples Abbreviations and acronyms:

LC / MS and HPLC methods: Method 1 (LC-MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 μ 50 x 1mm; mobile phase A: 1 l of water + 0.5 ml of 50% formic acid, mobile phase B: 1 l of acetonitrile + 0.5 ml of 50 % Concentration formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 1.5min 10% A → 2.2min 10% A oven: 50 ° C; flow rate: 0.33ml / min; UV detection: 210nm.

Method 2 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1mm; mobile phase A: 1 l of water + 0.25 ml of 99% formic acid, mobile phase B: 1 l of acetonitrile + 0.25 ml of Formic acid of 99% concentration; gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A oven: 50 ° C; flow rate: 0.40ml / min; UV detection: 210-400nm.

Method 3 (LC-MS):

MS instrument type: Waters Micromass Quattro Micro; HPLC instrument type: Agilent 1100 Series; column: Thermo Hypersil GOLD 3 μ 20mm x 4mm; mobile phase A: 1 l of water + 0.5 ml of 50% -concentrated formic acid, mobile phase B: 1l of acetonitrile + 0.5ml of 50% formic acid; gradient: 0.0min 100% A → 3.0min 10% A → 4.0min 10% A → 4.01min 100% A (flow rate 2.5ml / min) → 5.00min 100% A; Oven: 50 ° C; Flow rate: 2ml / min; UV detection: 210nm.

Method 4 (DCI-MS):

Apparatus: Thermo Fisher-Scientific DSQ; chemical free; reactant NH3 gas; source temperature: 200 ° C; free energy 70eV.

Method 5 (LC-MS):

MS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100 Series; column: Thermo Hypersil GOLD 3 μ 20 x 4 mm; mobile phase A: 1 l of water + 0.5 ml of 50% formic acid, mobile phase B : 1 l of acetonitrile + 0.5 ml of 50% formic acid; gradient: 0.0min 100% A → 3.0min 10% A → 4.0min 10% A; oven: 50 ° C; flow rate: 2ml / min; UV detection: 210nm .

Method 6 (GC-MS):

Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15m x 200μm x 0.33μm; constant helium flow rate: 0.88ml / min; oven: 70 ℃; inlet: 250 ℃; gradient: 70 ℃, 30 ℃ / min → 310 ° C (maintained for 3 min).

Method 7 (LC-MS):

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 μ 30 x 2mm; mobile phase A: 1 l of water + 0.25 ml of 99% formic acid, mobile phase B: 1 l of acetonitrile + 0.25 ml of Formic acid of 99% concentration; gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A oven: 50 ° C; flow rate: 0.60ml / min; UV detection: 208-400nm.

Method 8 (LC-MS):

MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: Zorbax SB-Aq (Agilent), 50mm x 2.1mm, 1.8 μm; mobile phase A: water + 0.025% formic acid, mobile phase B: acetonitrile (ULC) + 0.025% formic acid; gradient: 0.0min 98% A-0.9min 25% A-1.0min 5% A-1.4min 5% A-1.41min 98% A-1.5min 98% A; oven: 40 ° C; flow rate: 0.600 ml / min; UV detection: DAD; 210 nm.

Method 9 (Preparative HPLC):

Column: Macherey-Nagel VP 50/21 Nucleosil 100-5 C18 Nautilus. Flow rate: 25ml / min. Gradient: A = water + 0.1% concentrated ammonia, B = methanol, 0min = 30% B, 2min = 30% B, 6min = 100% B, 7min = 100% B, 7.1min = 30% B, 8min = 30% B, flow rate 25ml / min, UV detection 220nm.

Method 10 (FIA / MS, ES):

Apparatus: Waters ZQ 2000; electrospray free; mobile phase A: 1 l of water + 0.25 ml of 99% concentrated formic acid, mobile phase B: 1 l of acetonitrile + 0.25 ml of 99% concentrated formic acid; 25% A, 75% B ; Flow rate: 0.25ml / min.

Method 11:

MS instrument: Waters (Micromass) Quattro Micro; HPLC instrument: Agilent 1100 Series; column: YMC-Triart C18 3 μ 50 x 3 mm; mobile phase A: 1 l of water + 0.01 mol ammonium carbonate, mobile phase B: 1 l of acetonitrile ; Gradient: 0.0min 100% A → 2.75min 5% A → 4.5min 5% A; Oven: 40 ° C; Flow rate: 1.25ml / min; UV detection: 210nm.

Method 12 (Preparative LC-MS):

MS instrument: Waters, HPLC instrument: Waters (column Waters X-Bridge C18, 18mm x 50mm, 5μm, mobile phase A: water + 0.05% triethylamine, mobile phase B: acetonitrile (ULC) + 0.05% triethylamine , Gradient: 0.0min 95% A-0.15min 95% A-8.0min 5% A-9.0min 5% A; flow rate: 40ml / min; UV detection: DAD; 210-400nm). Or MS instrument: Waters, HPLC instrument: Waters (column Phenomenex Luna 5μ C18 (2) 100A, AXIA Tech. 50 x 21.2mm, mobile phase A: water + 0.05% formic acid, mobile phase B: acetonitrile (ULC) + 0.05 % Formic acid, gradient: 0.0min 95% A-0.15min 95% A-8.0min 5% A-9.0min 5% A; flow rate: 40ml / min; UV detection: DAD; 210-400nm).

Method 13

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 μ 50 x 1mm; mobile phase A: 1 l of water + 0.5 ml of 50% formic acid, mobile phase B: 1 l of acetonitrile + 0.5 ml of 50% concentration of formic acid; gradient: 0.0min 97% A → 0.5min 97% A → 3.2min 5% A → 4.0min 5% A Oven: 50 ° C; flow rate: 0.3ml / min; UV-detection: 210nm.

Method 14:

Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15m x 200μm x 0.33μm; constant helium flow rate: 1.20ml / min; oven: 60 ° C; inlet: 220 ° C; gradient: 60 ° C , 30 ℃ / min → 300 ℃ (maintain 3.33min).

Method 15:

MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100 Series; column: Agilent ZORBAX Extend-C18 3.0 x 50mm 3.5-micron; mobile phase A: 1 l of water + 0.01 mol ammonium carbonate, mobile phase B: 1 l Acetonitrile; gradient: 0.0min 98% A → 0.2min 98% A → 3.0min 5% A → 4.5min 5% A; oven: 40 ° C; flow rate: 1.75ml / min; UV detection: 210nm.

Method 16 (LC-MS):

Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 2.1 mm; Mobile phase A: 1 l of water + 0.25 ml 99% concentration of formic acid, mobile phase B: 1 l of acetonitrile + 0.25ml of 99% concentration of formic acid; gradient: 0.0min 90% A → 0.3min 90% A → 1.7min 5% A → 3.0min 5% A oven : 50 ° C; flow rate: 1.20ml / min; UV detection: 205-305nm.

If the compound of the present invention is purified by preparative HPLC according to the method described above, wherein the mobile phase contains additives such as trifluoroacetic acid, formic acid, or ammonia; if the compound of the present invention contains sufficient basic or acidic functional groups, the compound of the present invention It may contain a salt form, such as a trifluoroacetate, formate or ammonium salt. This salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.

Salts can be present in substoichiometric or superstoichiometric amounts, especially when amines or carboxylic acids are present. In addition, in the case of current imidazopyridines, salts may usually be present under acidic conditions, even in substoichiometric amounts, which are not shown from ¹ H NMR, and these related IUPAC names and Under the formula.

All ¹ H NMR spectral data are labeled with chemical shifts in ppm.

The multiplicity of proton signals in the ¹ H NMR spectrum in the following paragraphs indicates the signal form observed in each case and does not take into account any higher-order signal phenomena.

The methyl group of the chemical system "2-methylimidazo [1,2-a] pyridine" appears as a single peak in the ¹ H NMR spectrum (usually in DMSO-d ₆ and in the range of 2.40-2.60 ppm) And it can be clearly identified, or it is superimposed or completely under the solvent signal. In the ¹ H NMR spectrum, this signal can be marked in the expected way.

X-ray structure analysis:

Transmission Diffraction: Bruker Diffractometer with Apex-II-CCD Detector

Emissions: Copper, Kα

Main single light meter: Focus X-ray mirror

Measuring range: 4.73-67.08 °

Indoor conditions: 20 ℃

General operation process Representative operation process 1 Reduction of amino acids with lithium borohydride and trimethylchlorosilane

Initially, 1.7-2.5 equivalents of lithium borohydride are placed in THF (about 0.1-0.5M based on amino acid), 3.4-5.0 equivalents of trimethylchlorosilane (at 0 ° C or RT) are added and the mixture is placed at Stir at RT for 5 to 30 min. It was then carefully added in small portions at 0 ° C or RT, 1 equivalent of amino acid was added and the reaction mixture was stirred at RT overnight.

Exemplary follow-up of the reaction mixture: Methanol was added and the mixture was concentrated. A 20% potassium hydroxide solution was added to the residue and the mixture was extracted 3 times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

Representative operation process 2 Use TBTU as a coupling agent to form amidine

1 equivalent of the desired carboxylic acid (e.g. Example 3A), 1.1-1.5 equivalents of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU) and 3- 6 equivalents of 4-methylmorpholine are first placed in DMF or dichloromethane (about 0.1-0.2M based on the carboxylic acid to be coupled). 1.1 to 1.5 equivalents of the desired amine are then added and the mixture is stirred at RT overnight.

An exemplary subsequent treatment of the reaction mixture: adding water to the reaction solution and stirring the formed precipitate for 0.5-1.0 h, filtering, washing thoroughly with water and drying under high vacuum overnight. Alternatively, the reaction mixture can be directly concentrated, further purified by preparative HPLC and dried under high vacuum overnight.

If appropriate, the reaction mixture is filtered and the precipitate is washed with ether and dried under high vacuum.

If appropriate, the reaction mixture is diluted with ether, the precipitate is filtered and the filtrate is partitioned between ethyl acetate or dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate was concentrated and dried under high vacuum.

Representative operation process 3 Use HATU as a coupling agent to form amidine

1 equivalent of the desired carboxylic acid (e.g. Example 3A, 6A, 11A, 16A, 19A, 21A, 25A, 28A or 30A), 1.1 to 2.5 equivalents of O- (7-azabenzotriazole-1- Group) -N, N, N'N'-tetramethylthiofluorophosphoric acid (HATU) and 3 to 4 equivalents of N, N-diisopropylethylamine are first put into the DMF (approximately based on the desired carboxylic acid to be coupled), 1.2 to 2.0 equivalents of the desired amine is added and The mixture was stirred at RT until overnight.

Exemplary subsequent treatment of the reaction mixture: adding water to the reaction solution and stirring the formed precipitate for 30 min, filtering, washing thoroughly with water and drying under high vacuum overnight. In addition, after concentrating the reaction mixture under reduced pressure or directly after extraction treatment, the reaction mixture was further purified by preparative HPLC.

Envoys and intermediates: Example 1A 3-[(2,6-difluorobenzyl) oxy] pyridine-2-amine

At RT, 51 g of sodium methoxide (953 mmol, 1.05 equivalent) was first placed in 1000 ml of methanol, 100 g of 2-amino-3-hydroxypyridine (908 mmol, 1 equivalent) was added, and the mixture was stirred at RT for another 15 min. The reaction mixture was concentrated under reduced pressure, the residue was treated in 2500 ml of DMSO and 197 g of 2,6-difluorobenzyl bromide (953 mmol, 1.05 equivalent) was added. After 4 h at RT, the reaction mixture was poured into 20 l of water and stirred for 15 min, and the solid was filtered off. The solid was washed with 1 l of water, 100 ml of isopropanol and 500 ml of petroleum ether and dried under high vacuum. This gave 171 g of the title compound (78% of theory).

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.10 (s, 2 H); 5.52 (br.s, 2 H), 6.52 (dd, 1 H); 7.16-7.21 (m, 3 H); 7.49-7.56 (m, 2 H).

Example 2A 8-[(2,6-Difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

170 g of 3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine (Example 1A; 719 mmol, 1 equivalent) was first placed in 3800 ml of ethanol and 151 g of 3Å molecular sieve powder and 623 g of -Ethyl chloroacetamidine (3.6 mol, 5 eq). The reaction mixture was heated at reflux for 24 h and then filtered through silica gel and concentrated under reduced pressure. The mixture was kept at RT for 48 h, and the formed solid was filtered off. The solid was then stirred 3 times with a little isopropanol and then filtered and washed with ether. This gave 60.8 g (23% of theory) of the title compound. The filtrates from the combined filtration steps were concentrated and the residue was chromatographed on silica using cyclohexane / diethyl ether as the mobile phase. This gave an additional 46.5 g (18% of theory; total yield: 41% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.01min

MS (ESpos): m / z = 347 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.36 (t, 3 H); 2.54 (s, 3 H; DMSO signal is fuzzy); 4.36 (q, 2 H); 5.33 (s, 2 H); 7.11 (t, 1 H); 7.18-7.27 (m, 3 H); 7.59 (quint, 1 H); 8.88 (d, 1 H).

Example 3A 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

107 g of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 2A; 300 mmol, 1 equivalent) Dissolved in 2.8 l of THF / methanol (1: 1), added 1.5 l of a 1 N aqueous lithium hydroxide solution (1.5 mol, 5 eq) and stirred the mixture at RT for 16 h. The organic solvent was removed under reduced pressure, and the resulting aqueous solution was adjusted to a pH of 3-4 using an 1N aqueous hydrochloric acid solution on an ice bath. The resulting solid was filtered off, washed with water and isopropanol and dried under reduced pressure. This gave 92 g (95% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.62min

MS (ESpos): m / z = 319.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.55 (s, 3 H; overlap with DMSO signal); 5.32 (s, 2 H); 7.01 (t, 1 H); 7.09 (d, 1 H) ; 7.23 (t, 2 H); 7.59 (quint, 1 H); 9.01 (d, 1 H).

Example 4A 3- (cyclohexylmethoxy) pyridine-2-amine

At RT, place 96 g of a 45% strength aqueous solution of sodium hydroxide (1081 mmol, 1 equivalent) in 1170 ml of methanol, add 119 g of 2-amino-3-hydroxypyridine (1080 mmol, 1 equivalent) and place the mixture at RT Stir for 10 min. The reaction mixture was concentrated under reduced pressure. The residue was treated in 2900 ml of DMSO and 101 g of cyclohexylmethyl bromide (1135 mmol, 1.05 equivalent) was added. After 16 h at RT, the reaction mixture was slowly added to 6 l of water and the aqueous solution was extracted twice with 2 l of ethyl acetate each time. The combined organic phases were washed with 1 l of saturated aqueous sodium bicarbonate solution and water each time, dried, perchlorated and dried under reduced pressure. This gave 130 g (58% of theory) of the title compound.

LC-MS (Method 3): R _t = 1.41min

MS (ES +): m / z = 207.1 (M + H) ⁺

Example 5A 8- (Cyclohexylmethoxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

130 g of 3- (cyclohexylmethoxy) pyridin-2-amine (Example 4A; 630 mmol, 1 eq.) Were first placed in 3950 ml of ethanol, and 436 ml of ethyl 2-chloroacetamidoacetate (3.2 mol , 5 equivalents). The mixture was heated at reflux for 24 h and then concentrated under reduced pressure. The crude product obtained in this manner was chromatographed on silica gel using cyclohexane / diethyl ether as a mobile phase to obtain 66.2 g (33% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.17min

MS (ES +): m / z = 317.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.02-1.31 (m, 5 H); 1.36 (t, 3 H); 1.64-1.77 (m, 3 H); 1.79-1.90 (m, 3 H ); 2.60 (s, 3 H); 3.97 (d, 2 H); 4.35 (q, 2 H); 6.95 (d, 1 H); 7.03 (t, 1 H); 8.81 (d, 1 H).

Example 6A 8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

50 g of 8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 5A; 158 mmol, 1 equivalent) was dissolved in 600 ml of 1,4 -two To the alkane, 790 ml of a 2N aqueous sodium hydroxide solution (1.58 mol, 10 equivalents) were added and the mixture was stirred at RT for 16 h. 316 ml of 6N hydrochloric acid was added and the mixture was reduced to about 1/5 of the total volume. The resulting solid was filtered off, washed with water and tert-butyl methyl ether and dried under reduced pressure. This gave 35 g (74% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.81min

MS (ES +): m / z = 289.0 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.03-1.44 (m, 5 H); 1.64-1.78 (m, 3 H); 1.81-1.92 (m, 3 H); 2.69 (s, 3 H ); 4.07 (d, 2 H); 7.30-7.36 (m, 2 H); 9.01 (d, 1 H).

Example 7A 5-fluoro-2-nitropyridin-3-ol

Under ice cooling, 5 g of 5-fluoropyridin-3-ol (44 mmol, 1 equivalent) was dissolved in 43 ml of concentrated sulfuric acid, and 2.8 ml of concentrated nitric acid was added at 0 ° C over a period of 5 minutes. Will counter It should be warmed to RT and kept stirring until overnight. The mixture was added to 100 g of ice and stirred for 30 min. The obtained solid was filtered off and dried under reduced pressure. This gave 5.6 g (81% of theory) of the title compound, which was used in the next reaction without further purification.

LC-MS (Method 2): R _t = 0.45min

MS (ESneg): m / z = 156.9 (MH) ^-

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 7.5 (dd, 1 H); 8.08 (d, 1 H); 12.2 (br.s, 1 H).

Example 8A 2-amino-5-fluoropyridin-3-ol

5.6 g of 5-fluoro-2-nitropyridin-3-ol (Example 7A; 36 mmol) was dissolved in 2 l of ethanol, a catalytic amount of activated carbon was added to the palladium (10%) and the mixture was hydrogenated under standard hydrogen pressure. 16h. The mixture was filtered through silica gel and the filtrate was concentrated (product batch 1). The filter cake was rinsed with methanol until the color of the filtrate was no longer yellow. The filtrate was concentrated to give a second crop. This gave 4.26 g (85% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.17min

MS (ES +): m / z = 128.9 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.4 (br.s, 2 H); 6.8 (dd, 1 H); 7.4 (d, 1 H).

Example 9A 6-fluoro-8-hydroxy-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

3.2 g of 2-amino-5-fluoropyridin-3-ol (Example 8A; 25 mmol, 1 equivalent) First put in 155 ml of ethanol, add 1.5 g of 3Å molecular sieve powder and 20.6 g of ethyl 2-chloroacetamidoacetate (125 mmol, 5 equivalents) and boil the mixture to reflux overnight. The reaction solution was concentrated and chromatographed (Biotage Isolera Four; SNAP Cartridge KP-Sil 50 g; cyclohexane / ethyl acetate gradient; then dichloromethane / methanol gradient). The crude product was partially dissolved in a little methanol and tertiary butyl methyl ether was added. The solid was filtered off and washed with tert-butyl methyl ether. This gave 570 mg (10% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 239.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.39 (t, 3 H); 2.64 (s, 3 H); 4.40 (q, 2 H); 7.20 (br.d, 1 H); 8.9 ( dd, 1 H); 12.5 (br.s, 1 H).

Example 10A 8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

560 mg of ethyl 6-fluoro-8-hydroxy-2-methylimidazo [1,2-a] pyridine-3 carboxylate (Example 9A; 2.4 mmol, 1.0 equivalent), 1.7 g of cesium carbonate (5.17 mmol , 2.2 equivalents) and 535 mg of 2,6-difluorobenzyl bromide (2.6 mmol, 1.1 equivalents) were first put into 34 ml of anhydrous DMF, and the mixture was heated at 50 ° C. for 15 min. Water was added, the mixture was stirred for 30 min and the solid was filtered off and washed with water. This gave 560 mg of the title compound (65% of theory).

LC-MS (Method 2): R _t = 1.18min

MS (ES +): m / z = 365.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (t, 3 H); 2.55 (s, 3 H; overlap with DMSO signal); 4.38 (q, 2 H); 5.89 (s, 2 H) ; 7.23 (t, 2 H); 7.44 (dd, 1 H); 7.60 (q, 1 H); 8.90 (dd, 1 H).

Example 11A 8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

550 mg of 8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 10A; 1.5 mmol, 1 equivalent) was dissolved in 64 ml of THF and 12 ml of methanol, 7.5 ml of a 1 N aqueous lithium hydroxide solution was added and the mixture was stirred at RT overnight. Then 8 ml of a 1N aqueous hydrochloric acid solution was added, and the mixture was concentrated under reduced pressure. The formed solid was filtered off and washed with water. This gave 429 mg of the title compound (80% of theory).

LC-MS (Method 1): R _t = 0.90min

MS (ES +): m / z = 337.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.54 (s, 3 H; overlap with DMSO signal); 5.84 (s, 2 H); 7.23 (t, 2 H); 7.40 (dd, 1 H) ; 7.51 (q, 1 H); 8.92 (dd, 1 H); 13.28 (br.s, 1 H).

Example 12A 5-chloro-2-nitropyridin-3-ol

Under ice cooling, 30 g of 5-chloropyridin-3-ol (232 mmol, 1 equivalent) was dissolved in 228 ml of concentrated sulfuric acid, and 24 ml of concentrated nitric acid was slowly added at 0 ° C. The reaction was warmed to RT, stirred overnight and then into the ice / water mixture and stirred for another 30 min. The solid was filtered off, washed with cold water and air-dried. This gave 33 g (82% of theory) of the title compound, which was used in the next reaction without further purification.

LC-MS (Method 2): R _t = 0.60min

MS (ES-): m / z = 172.9 / 174.9 (MH) ^-

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 7.71 (d, 1 H); 8.10 (d, 1 H); 12.14 (br.1 H).

Example 13A 5-chloro-3-[(2,6-difluorobenzyl) oxy] -2-nitropyridine

33 g of 5-chloro-2-nitropyridin-3-ol (Example 12A; 189 mmol, 1 equivalent) and 61.6 g of cesium carbonate (189 mmol, 1 equivalent) were first put into 528 ml of DMF, and 40.4 g of 2, 6-Difluorobenzyl bromide (189 mmol, 1 eq.) And the mixture was stirred at RT overnight. The reaction mixture was stirred into water / 1N aqueous hydrochloric acid. The solid was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.46 (s, 2 H); 7.22 (t, 2 H); 7.58 (q, 1 H); 8.28 (d, 1 H); 8.47 (d, 1 H).

Example 14A 5-chloro-3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine

59.7 g of 5-chloro-3-[(2,6-difluorobenzyl) oxy] -2-nitropyridine (Example 13A; 199 mmol, 1 equivalent) was first placed in 600 ml of ethanol and 34.4 g Iron powder (616 mmol, 3.1 equivalents) and the mixture was heated at reflux. 152 ml of concentrated hydrochloric acid was slowly added dropwise and the mixture was refluxed for another 30 min under boiling. The reaction mixture was cooled and stirred into an ice / water mixture. The resulting mixture was adjusted to pH 5 using sodium acetate. The solid was filtered off, washed with water and air-dried and then dried under reduced pressure at 50 ° C. This gave 52.7 g (98% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.93min

MS (ES +): m / z = 271.1 / 273.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.14 (s, 2 H); 5.82 (br.s, 2 H); 7.20 (t, 2 H); 7.35 (d, 1 H); 7.55 ( q, 1 H); 7.56 (d, 1 H).

Example 15A 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

40 g of 5-chloro-3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine (Example 14A; 147.8 mmol; 1 equivalent) was first placed in 800 ml of ethanol, and 30 g of 3Å molecular sieve was added Fanhe 128 g of ethyl 2-chloroacetamidine (739 mmol, 5 eq.) And the mixture was heated to reflux overnight. The reaction mixture was concentrated and the residue was treated in ethyl acetate and filtered. The ethyl acetate phase was washed with water, dried, filtered and concentrated. This gave 44 g (78% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.27min

MS (ES +): m / z = 381.2 / 383.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.36 (t, 3 H); 2.54 (s, 3 H; hidden by DMSO signal); 4.37 (q, 2 H); 5.36 (s, 2 H) ; 7.26 (t, 2 H); 7.38 (d, 1 H); 7.62 (q, 1 H); 8.92 (d, 1 H).

Example 16A 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

44 g of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 15A; 115 mmol , 1 equivalent) was dissolved in 550 ml of THF and 700 ml of methanol, 13.8 g of lithium hydroxide (dissolved in 150 ml of water; 577 mmol, 5 equivalents) was added and the mixture was stirred at RT overnight. A 1N aqueous hydrochloric acid solution was added and the mixture was concentrated under reduced pressure. The resulting solid was filtered off and washed with water. This gave 34 g of the title compound (84% of theory).

LC-MS (Method 1): R _t = 1.03min

MS (ES +): m / z = 353.0 / 355.0 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.54 (s, 3 H; overlap with DMSO signal); 5.36 (s, 2 H); 7.26 (t, 2 H); 7.34 (d, 1 H) ; 7.61 (q, 1 H); 8.99 (d, 1 H); 13.36 (br.s, 1 H).

Example 17A 5-bromo-3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine

32.6 g of 3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine (Example 1A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulfuric acid, and the mixture was cooled to 0 ° C. . 8.5 ml of bromine (165 mmol, 1.2 equivalents) was dissolved in 85 ml of acetic acid and then added dropwise to the ice-cooled reaction solution over a period of 90 min. After the dropwise addition was completed, the mixture was stirred at 0 ° C for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether / ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.96min

MS (ES +): m / z = 315.1 / 317.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.14 (s, 2 H); 5.83 (br.s, 2 H); 7.20 (t, 2 H); 7.42 (d, 1 H); 7.54 ( q, 1 H); 7.62 (d, 1 H).

Example 18A 6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

16 g of 3Å molecular sieve powder and 52.7 ml of ethyl 2-chloroacetamidoacetate (380.8 mmol; 5 eq) were added to 24 g of 5-bromo-3-[(2,6-difluorobenzyl) oxy] Pyridine-2-amine (Example 17A; 76.2 mmol; 1 equivalent) in 400 ml of an ethanol solution, and the mixture was heated to reflux overnight. An additional 8 g of molecular sieve was added and the mixture was heated at reflux for another 24 h. The reaction mixture was concentrated under reduced pressure and the residue was treated in dichloromethane and chromatographed on silica gel (dichloromethane / methanol 20: 1 as mobile phase). The product-containing fractions were concentrated and the residue was stirred with 100 ml of ether for 30 min. The product was then filtered off, washed with a little ether and dried. This gave 15 g (45% of theory) of the title compound.

LC-MS (Method 1): R _t = 1.43min

MS (ES +): m / z = 414.9 / 416.8 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.36 (t, 3 H); 2.54 (s, 3 H; hidden by DMSO signal); 4.37 (q, 2 H); 5.36 (s, 2 H) ; 7.25 (t, 2 H); 7.42 (d, 1 H); 7.61 (q, 1 H); 9.00 (d, 1 H).

Example 19A 6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

1.5 g of 6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 18A; 3.5 mmol, 1 equivalent) was dissolved in 72 ml of 5: 1 THF / methanol, 17.6 ml of a 1 N aqueous lithium hydroxide solution (17.6 mmol, 5 equivalents) were added and the mixture was warmed to 40 ° C. and stirred at this temperature for 6 h. The mixture was then adjusted to pH 4 using a 6N aqueous hydrochloric acid solution and concentrated under reduced pressure. Water was added to the formed solid and the solid was triturated, filtered, washed with water and dried under reduced pressure. This gave 1.24 g of the title compound (88% of theory).

LC-MS (Method 2): R _t = 0.93min

MS (ES +): m / z = 397.0 / 399.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.54 (s, 3 H; overlaps with DMSO signal); 5.36 (s, 2 H); 7.25 (t, 2 H); 7.40 (d, 1 H) ; 7.61 (q, 1 H); 9.06 (d, 1 H); 13.35 (br.s, 1 H).

Example 20A 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

20.00 g (85.38 mmol) of 8-hydroxy-2,6-dimethyl from Example 239A Imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester, 19.44 g (93.91 mmol) of 2,6-difluorobenzyl bromide and 61.20 g (187.83 mmol) of cesium carbonate in 1.18 l of DMF Stir at 60 ° C for 5h. The reaction mixture was then poured into a 10% strength sodium chloride aqueous solution at 6.41 and then extracted twice with ethyl acetate. The combined organic phases were washed with 854 ml of a 10% strength sodium chloride aqueous solution, dried, concentrated, and dried under high vacuum at RT overnight. This gave 28.2 g (92% of theory; purity of about 90%) of the title compound.

LC-MS (Method 2): R _t = 1.05min

MS (ES +): m / z = 361.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.38 (t, 3 H); 2.36 (s, 3 H); 4.35 (q, 2 H); 5.30 (s, 2 H); 7.10 (s, 1 H); 7.23 (t, 2 H); 7.59 (q, 1 H); 8.70 (s, 1 H).

Example 21A 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid

220 mg of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 20A; 0.524 mmol , 1 equivalent) was dissolved in 7 ml of 1: 1 THF / methanol, 2.6 ml of a 1 N aqueous lithium hydroxide solution (2.6 mmol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure and the residue was acidified with a 1 N aqueous hydrochloric acid solution and stirred for 15 min. The solid was filtered off, washed with water and dried under reduced pressure. This gave 120 mg of the title compound (60% of theory).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 333.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.34 (s, 3 H); 5.28 (s, 2 H); 7.09 (s, 1 H); 7.23 (t, 2 H); 7.58 (q, 1 H); 8.76 (s, 1 H); 13.1 (br.s, 1 H), [the other signal is hidden under the DMSO signal].

Example 22A 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carbonyl hydrochloride

Add 4 drops of DMF to 2.0 g of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (6.28 mmol, 1 eq.) Of 25 ml of anhydrous THF solution, followed by the dropwise addition of 3.19 g of chloramphenicol (25.14 mmol, 4 eq.). The reaction mixture was stirred at RT for 3 h. An additional 0.80 g of chloramphetamine (6.28 mmol, 1 eq) was added and the reaction was stirred at RT for another 4 h. The reaction mixture was concentrated and co-evaporated three times with toluene, and the residue was dried under high vacuum, thereby obtaining 2.43 g of the title compound (103% of theory).

DCI-MS (Method 4): MS (ES +): m / z = 437 (M-HCl + H) ⁺

Example 23A Ethyl 2-chloro-3-cyclopropyl-3-oxopropanoate

3.1 ml of thionyl chloride (38.2 mmol, 1.05 equivalents) was first placed in 21 ml of dichloromethane, and 5.68 g of ethyl 3-cyclopropyl-3-pentoxypropionate (36.4) was added dropwise on a water bath. mmol). The reaction mixture was stirred at RT for 2h. The mixture was then mixed with water, 5% carbonic acid The aqueous sodium hydrogen solution and the saturated aqueous sodium chloride solution were washed, dried over magnesium sulfate and concentrated. The crude product (6.8 g) was used in the next reaction without further purification.

Example 24A 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

1.69 g of 3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine (Example 1A; 7.13 mmol, 1 equivalent) was first placed in 44.4 ml of ethanol, and 425 mg of 3Å molecular sieve Powder and 6.8 g of ethyl 2-chloro-3-cyclopropyl-3-pentoxypropanoate (crude product from Example 23A). The reaction mixture was heated at reflux for 48 h and then concentrated under reduced pressure and the residue was chromatographed (cyclohexane / ethyl acetate as mobile phase). The product-containing fractions were combined and concentrated under reduced pressure. The residue obtained in this way was treated with methanol, DMSO and water. The obtained solid was filtered off and dried under high vacuum to obtain 410 mg (15.4% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.22min

MS (ES +): m / z = 373.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.95-1.05 (m, 4 H); 1.39 (t, 3 H); 2.36 (s, 3 H); 2.70-2.80 (m, 1 H); 4.39 (q, 2 H); 5.30 (s, 2 H); 7.08 (t, 1 H); 7.15 (d, 1 H); 7.20 (t, 2 H); 7.59 (q, 1 H); 8.88 ( d, 1 H).

Example 25A 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid

410 mg of 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 24A, 1.1 mmol, 1 (Equivalent) was first placed in 15 ml of methanol / THF (1: 1), and 5.5 ml of a 1 N aqueous lithium hydroxide solution (5.5 mmol, 5 equivalents) were added. The reaction mixture was stirred at RT overnight. An additional 5.5 ml of a 1 N aqueous lithium hydroxide solution was added, and the mixture was stirred at RT for another night. The mixture was then concentrated under reduced pressure and the residue was treated with water and acidified with 1N aqueous hydrochloric acid. The precipitated product was filtered off and dried under high vacuum. This gave 293 mg (77% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.83min

MS (ES +): m / z = 345.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.95-1.02 (m, 4 H); 2.80 (q, 1 H); 5.30 (s, 2 H); 7.02 (t, 1 H); 7.15 ( d, 1 H); 7.22 (t, 2 H); 7.59 (q, 1 H); 8.92 (s, 1 H); 13.3 (br.s, 1 H).

Example 26A 2-Chloro-3-lanthoxy propionate

139 ml of a 21% strength sodium ethoxide in ethanol solution (371 mmol, 0.91 equivalent) was first placed in 200 ml of diethyl ether, and 43.7 ml of ethyl chloroacetate (408 mmol, 1 equivalent) and 32.9 ml of ethyl formate (408 mmol, 1 equivalent) in 150 ml of ether. The reaction mixture was stirred overnight and the solid was filtered off and washed with ether. The solid was dissolved in water and the aqueous phase was adjusted to pH 4 using concentrated hydrochloric acid while cooling in an ice bath. The mixture was repeatedly extracted with ether and the combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The resulting crude product (8.2 g) was removed under high vacuum for residual solvent and used in the next reaction without further purification.

Example 27A 8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

1.93 g of 3-[(2,6-difluorobenzyl) oxy] pyridin-2-amine (Example 1A; 8.2 mmol, 1 equivalent) was first placed in 50 ml of ethanol, and 8.2 g of 2- Ethyl chloro-3-oxopropionate (75% purity, crude product from Example 26A, 40.8 mmol, 5 eq.). The reaction mixture was heated to reflux overnight. The mixture was then concentrated under reduced pressure and the resulting crude product was chromatographed on 340 g of silica gel (Biotage Isolera) (mobile phase: cyclohexane: ethyl acetate gradient; the product was in cyclohexane: ethyl acetate 2: 1) (R _f value = 0.36). The product fractions were combined and concentrated and the resulting residue was triturated with diisopropyl ether. The solid was filtered off and dried under high vacuum. This gave 2.02 g of the title compound (71% of theory).

LC-MS (Method 2): R _t = 1.08min

MS (ES +): m / z = 333.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.35 (t, 3 H); 4.39 (q, 2 H); 5.35 (s, 2 H); 7.15-7.28 (m, 4 H); 7.58 ( q, 1 H); 8.18 (s, 1 H); 8.90 (d, 1 H).

Example 28A 8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid

1 g of 8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (Example 27A, 3 mmol, 1 equivalent) was first placed in 60 ml of In methanol / THF (5: 1), 15 ml of a 1 N aqueous lithium hydroxide solution (15 mmol, 5 equivalents) were added and the mixture was warmed to 40 ° C and stirred at this temperature for 4 h. The mixture was then cooled and adjusted to pH 4 using 6N aqueous hydrochloric acid solution under ice cooling. The organic solvent was removed on a rotary evaporator, water was added to the precipitated product and the product was filtered, washed with water and dried under high vacuum. This gave 797 mg (87% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.66min

MS (ES +): m / z = 305.1 (M + H) ⁺

1H NMR (400MHz, DMSO-d6): δ = 5.38 (s, 2 H); 7.10-7.28 (m, 4 H); 7.59 (q, 1 H); 8.12 (s, 1 H); 8.92 (s, 1 H); 13.1 (br.s, 1 H).

Example 29A 8- (Benzyloxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 eq.) Were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetamidoacetate (624.2 mmol, 5 eq.) And 15g of 4Å molecular sieve. The mixture was heated at reflux for 2 days (bath temperature 100 ° C). The mixture was then cooled and the excess of ethyl 2-chloroacetamidoacetate was evaporated on a rotary evaporator in a dry ice bath. The residue was purified by silica gel chromatography (mobile phase cyclohexane: ethyl acetate 9: 1, 4: 1). This gave 20.81 g of the title compound (54% of theory).

LC-MS (Method 1): R _t = 1.12min

MS (ES +): m / z = 311 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.35 (t, 3H), 2.59 (s, 3H), 4.34 (q, 2H), 5.32 (s, 2H), 7.01-7.09 (m, 2H) , 7.33-7.48 (m, 3H), 7.52 (d, 2H), 8.81-8.86 (m, 1H).

Example 30A 8- (benzyloxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

253 ml of a 2N aqueous sodium hydroxide solution was added to 15.7 g of 8- (benzyloxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (50.59 mmol) in 253 ml of 1 , 4-two In alkane solution, and the mixture was stirred at RT for 14 h. Then, 101 ml of a 6N aqueous hydrochloric acid solution was added. The formed solid was filtered off, washed with water and methyl tert-butyl ether and then dried at 40 ° C under reduced pressure overnight. This gave 15.49 g (108% of theory) of 8- (benzyloxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid.

LC-MS (Method 1): R _t = 0.66min

MS (ES +): m / z = 283.0 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.67 (s, 3H), 3.2-3.8 (very broad water wave), 5.41 (s, 2H), 7.30 (m, 1H), 7.35-7.48 ( m, 4H), 7.57 (d, 2H), 9.02 (d, 1H).

Example 31A Racemic-2-amino-4,4,4-trifluorobut-1-ol

0.32 ml of lithium borohydride (2M in THF, 0.65 mmol, 2.5 eq.) Was first placed in 0.5 ml of anhydrous THF, 0.16 ml of trimethylchlorosilane (1.28 mmol, 5 eq.) Was added at RT, and the mixture was Stir at RT for 5 min. Then added in small portions at a time, 50 mg of 2-amino-4,4,4-trifluorobutyrate (0.26 mmol, 1 equivalent) was added and the reaction mixture was stirred at RT overnight. 0.5 ml of methanol was added, and then the mixture was concentrated. Then, 0.6 ml of a 20% strength potassium hydroxide solution was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 33 mg of the title compound (88% of theory).

DCI-MS (Method 4): MS (ES +): m / z = 144 (M + H) +

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.08-2.20 (m, 1H), 2.22-2.38 (m, 1H), 3.25-3.32 (m, 1H), 3.39-3.44 (m, 1H), 3.59-3.65 (m, 1H).

The examples shown in Table 1A are similar to Example 31A prepared by reacting lithium borohydride (1.7-2.5 equivalents) and trimethylchlorosilane (3.4-5 equivalents) with a suitable commercially available amino acid according to the general operating procedure 1:

Example 34A Racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (4,4,4-trifluoro-1-hydroxybut-2-yl) imidazo [ 1,2-a] pyridine-3-carboxamide

330 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (1.04 mmol), 399 mg of (benzotris Azole-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 1.24 mmol) and 524 mg of 4-methylmorpholine (5.18 mmol) were first placed in 6.6 ml of DMF. After 10 min at RT, 371 mg (1.56 mmol, purity about 60%) of 2-amino-4,4,4-trifluorobut-1-ol (Example 31A) was added and the mixture was stirred at RT overnight. About 200 ml of water was added, the reaction solution was stirred for another 30 min and the formed precipitate was filtered off, washed with water and dried under high vacuum overnight. This gave 439 mg of the title compound (96% of theory).

LC-MS (Method 5): R _t = 1.62min

MS (ES +): m / z = 444 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.50 (s, 3H), 2.55-2.72 (m, 2H), 3.38-3.47 (m, 1H), 3.51-3.62 (m, 1H), 4.29- 4.40 (m, 1H), 5.12 (t, 1H), 5.30 (s, 2H), 6.92 (t, 1H), 7.02 (d, 1H), 7.23 (t, 2H), 7.59 (quint, 1H), 7.80 (d, 1H), 8.56 (d, 1H).

The examples shown in Table 2A are similar to Example 34A by 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid with appropriate A commercially available amino acid is prepared by reacting under the reaction conditions described in General Procedure 2:

a) Alternative follow-up: The crude reaction mixture was purified directly by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA).

Example 37A Racemic-N- (1-chloro-4,4,4-trifluorobut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide hydrochloride

2.48 g of racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (4,4,4-trifluoro-1-hydroxybut-2-yl ) Imidazolo- [1,2-a] pyridine-3-carboxamide (Example 34A, 5.59 mmol) was first placed in dichloromethane. 1.22 ml of thionyl chloride (16.77 mmol) was added dropwise at 0 ° C, and the mixture was stirred at RT overnight. The reaction solution was concentrated and dried under high vacuum. This gave 2.78 g of the title compound (99.8% of theory).

LC-MS (Method 2): R _t = 0.94min

MS (ES +): m / z = 462 (M-HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.60 (s, 3H), 2.70-2.84 (m, 2H), 3.82-3.92 (m, 2H), 4.55-4.67 (m, 1H), 5.43 ( s, 2H), 7.23 (t, 2H), 7.31-7.43 (m, 1H), 7.51-7.66 (m, 2H), 8.63 (d, 1H), 8.82 (br s, 1H).

The examples shown in Table 3A were prepared similarly to Example 37A.

Example 41A Racemic-N- (1-azido-4,4,4-trifluorobut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamide

195 mg of racemic-N- (1-chloro-4,4,4-trifluorobut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methyl Imidazo [1,2-a] pyridine-3-carboxamide hydrochloride (Example 37A, 0.39 mmol) was first placed in 3.4 ml of DMF, 254 mg of sodium azide (3.91 mmol) was added and the mixture was dissolved in Stir for 4h at ℃. The mixture was then stirred at 60 ° C for 5 h. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and The residue was purified by silica gel chromatography (mobile phase: cyclohexane: ethyl acetate 7: 3, isocratic). This gave 50 mg of the title compound (27% of theory).

LC-MS (Method 2): R _t = 0.97min

MS (ES +): m / z = 469 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.50 (s, 3H), 2.58-2.78 (m, 2H), 3.52-3.63 (m, 2H), 4.47-4.58 (m, 1H), 5.30 ( s, 2H), 6.93 (t, 1H), 7.02 (d, 1H), 7.22 (t, 2H), 7.59 (quint, 1H), 8.09 (d, 1H), 8.55 (d, 1H).

The examples shown in Table 4A were prepared similarly to Example 41A by reacting sodium azide (5-20 equivalents) with the appropriate chloride. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane: ethyl acetate gradient or isocratic).

a) Use 20 equivalents of sodium azide

Example 45A Racemic- [2- (4-chlorophenyl) -2-hydroxyethyl] carbamic acid third butyl ester

First, 2.43 g of triethylamine (24.03 mmol) and then 2.35 g of di-third-butyl dicarbonate (10.76 mmol) were added to 2.0 g of racemic-2-amino-1- (4- (Chlorophenyl) ethanol hydrochloride (9.61 mmol) in 14 ml of dichloromethane. The reaction mixture was stirred at RT for 2h. The mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, concentrated under reduced pressure and dried under high vacuum. This gave 2.72 g of the title compound (104% of theory).

LC-MS (Method 2): R _t = 0.97min

MS (ES-): m / z = 272 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.33 (s, 9H), 2.97-3.13 (m, 2H), 4.54-4.62 (m, 1H), 5.44 (d, 1H), 6.73 (t, 1H), 7.31 (d, 2H), 7.38 (d, 2H).

The examples shown in Table 5A are similar to Example 45A prepared by reacting di-t-butyl dicarbonate in dichloromethane with a suitable commercially available amine.

Example 47A Racemic-3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3- (4-fluorophenyl) propionic acid

2.0 g of racemic-3-amino-3- (4-fluorophenyl) propionic acid (10.92 mmol) and 1.62 g of phthalic anhydride (10.92 mmol) were dissolved in 9 ml of DMF and heated to reflux at 135 ° C to Overnight. The reaction solution was added to about 200 ml of water. The formed solid was stirred at RT for about 30 min and then filtered, washed with water and dried under high vacuum. This gave 3.43 g of the title compound (86% of theory, purity 86%).

LC-MS (Method 1): R _t = 1.09min

MS (ES +): m / z = 314 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.24-3.3.34 (m, 1H), 3.44-3.53 (m, 1H), 5.63-5.70 (m, 1H), 7.18 (t, 2H), 7.48 (dd, 1H), 7.82-7.90 (m, 4H), 12.48 (br s, 1H).

Example 48A Racemic-3- (3,4-difluorophenyl) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propionic acid

step 1:

Under argon, 697 g of 3,4-difluorobenzaldehyde (4.76 mol, 1 equivalent), 495 g of malonic acid (4.76 mol, 1 equivalent) and 733 g of amine acetate (9.52 mol, 2 equivalents) were stirred under reflux in 2788 ml of ethanol for 20 h. The mixture was then cooled to RT and stirred overnight at RT. The precipitated crystals were filtered by suction, washed with ethanol and ether and dried under reduced pressure. This gave 590 g (62% of theory) of racemic-3-amino-3- (3,4-difluorophenyl) propionic acid.

Racemic-3-amino-3- (3,4-difluorophenyl) propionic acid: LC-MS (Method 1): R _t = 0.27min

MS (ES +): m / z = 202.0 (M + H) ⁺

Step 2:

Dissolve 0.20 g (0.99 mmol) of racemic-3-amino-3- (3,4-difluorophenyl) propionic acid and 0.15 g (0.99 mmol) of phthalic anhydride in 0.8 ml of DMF and dissolve in 135 Heated to reflux overnight. The reaction solution was added to about 9 ml of water. The resulting suspension was extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 0.2 g of the title compound (61% of theory).

LC-MS (Method 2): R _t = 0.97min

MS (ES +): m / z = 332 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.24-3.3.33 (m, 1H), 3.44-3.52 (m, 1H), 5.63-5.70 (m, 1H), 7.23-7.28 (m, 1H ), 7.36-7.47 (m, 1H), 7.49-7.57 (m, 1H), 7.82-7.90 (m, 4H), 12.51 (br s, 1H).

Example 49A Racemic-3- (2,4-difluorophenyl) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propionic acid

5.0 g of racemic-3-amino-3- (2,4-difluorophenyl) propionic acid (24.85 mmol) and 3.68 g of phthalic anhydride (24.85 mmol) were dissolved in 20 ml of DMF and the mixture was dissolved in Heat to reflux at 135 ° C overnight. The reaction solution was added to about 160 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 80: 1, isocratic) and then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). This gave 3.43 g of the title compound (27% of theory).

LC-MS (Method 1): R _t = 1.11min

MS (ES +): m / z = 332 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.24-3.3.34 (m, 1H), 3.40-3.49 (m, 1H), 5.89 (t, 1H), 7.09-7.15 (m, 1H), 7.19-7.28 (m, 1H), 7.70 (q, 1H), 7.82-7.89 (m, 4H), 12.55 (br s, 1H).

Example 50A Racemic- [2- (4-chlorophenyl) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] carbamic acid Tributyl ester

At RT, 2.61 g of racemic- [2- (4-chlorophenyl) -2-hydroxyethyl] carbamic acid third butyl ester (Example 45A, 9.62 mmol) and 1.42 g of phthalimidine ( 9.62 mmol) and 3.78 g of triphenylphosphine (14.43 mmol) were first placed in anhydrous THF. Then 4.03 g (14.43 mmol) of diisopropyl azodicarboxylate was added dropwise, and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane: ethyl acetate 10: 1). This gave 2.92 g of the title compound (55% of theory, purity 73%).

LC-MS (Method 2): R _t = 1.22min

MS (ES +): m / z = 401 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.26 (s, 9H), 3.70-3.79 (m, 1H), 3.82-3.93 (m, 1H), 5.32-5.38 (m, 1H), 7.22 ( t, 1H), 7.38-7.44 (m, 4H), 7.80-7.85 (m, 4H).

The examples shown in Table 6A are similar to Example 50A prepared by reacting phthalimide, triphenylphosphine, and diisopropyl azodicarboxylate in THF with a suitable alcohol.

Example 52A Racemic- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -2- (4-fluorophenyl) ethyl] carbamic acid Tributyl ester

Under argon, 3.2g of racemic-3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3- (4-fluoro Phenyl) propionic acid (Example 47A, 8.78 mmol) in 32 ml of a toluene solution, and 1.33 g of triethylamine (13.18 mmol) and 98 mg of 1,4-diazabicyclo [2.2.2] octane ( 0.88 mmol), 3.14 g of diphenyl azide phosphate (11.42 mmol) and 6.51 g of tertiary butanol (87.84 mmol). The reaction mixture was heated to reflux overnight and then diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 8: 1; 6: 1). This gave 959 mg of the title compound (28% of theory).

LC-MS (Method 2): R _t = 1.11min

MS (ES +): m / z = 385 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.26 (s, 9H), 3.69-3.78 (m, 1H), 3.84-3.95 (m, 1H), 5.32-5.39 (m, 1H), 7.15- 7.26 (m, 3H), 7.41-7.48 (m, 2H), 7.80-7.89 (m, 4H).

Example 53A Racemic- [2- (3,4-difluorophenyl) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] Tert-butyl carbamate

Under argon, 5.0g of racemic-3- (3,4-difluorophenyl) -3- (1,3-dioxo-1,3-dihydro-2H-iso Indol-2-yl) propionic acid (Example 48A, 15.09 mmol) and 3.06 g of triethylamine (30.19 mmol) in 65 ml of a toluene solution, 4.36 g of diphenyl azide phosphate (15.85 mmol) were added and the mixture Stir at RT for 3.5 h. Then 65 ml of tert-butanol was added and the mixture was stirred under reflux overnight. After cooling, the reaction solution was concentrated and purified by flash chromatography (mobile phase: petroleum ether / ethyl acetate 2: 1, isocratic). This gave 3.1 g of the title compound (45% of theory).

LC-MS (Method 2): R _t = 1.19min

MS (ES +): m / z = 403 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.26 (s, 9H), 3.73-3.90 (m, 2H), 5.32-5.39 (m, 1H), 7.20-7.27 (m, 2H), 7.36- 7.46 (m, 1H), 7.48-7.56 (m, 1H), 7.81-7.91 (m, 4H).

Example 54A Racemic- [2- (2,4-difluorophenyl) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] Tert-butyl carbamate

Under argon, 2.17 g of racemic-3- (2,4-difluorophenyl) -3- (1,3-dioxo-1,3-dihydro-2H-isoindole 2-yl) propionic acid (Example 49A, 6.54 mmol) and 1.32 g of triethylamine (13.07 mmol) were first placed in 23.8 ml of anhydrous toluene. At RT, 1.89 g of diphenyl azide phosphate (6.86 mmol) was added, and the mixture was stirred at RT to cool with water for 3.5 h, then 23.8 ml of tert-butanol was added and the mixture was stirred under reflux overnight. After cooling, the reaction solution was concentrated and purified by flash chromatography (mobile phase: cyclohexane / ethyl acetate 2: 1). This gave 650 mg of the title compound (24% of theory).

LC-MS (Method 2): R _t = 1.11min

MS (ES +): m / z = 403 (M + H) ⁺

Example 55A Racemic- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester

6.13 g of racemic- [2- (3,4-difluorophenyl) -2- (1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl ) Ethyl] -carbamic acid third butyl ester (Example 53A, purity about 60%, about 9.14 mmol) was first put into 13.1 ml of a 40% strength methylamine aqueous solution and stirred in a closed container at 60 ° C. overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane: methanol: diethylamine 30: 1: 0.1; 20: 1: 0.1). This gave 1.83 g of the title compound (74% of theory).

LC-MS (Method 1): R _t = 0.65min

MS (ES +): m / z = 273 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.33 (s, 9H), 1.96 (br s, 2H), 2.92-3.10 (m, 2H), 3.81-3.88 (m, 1H), 6.76-6.82 (m, 1H), 7.11-7.17 (m, 1H), 7.27-7.40 (m, 2H).

The examples shown in Table 7A were prepared similarly to Example 55A by reacting methylamine with a suitable phthalimide.

¹⁾ The obtained crude product was concentrated and repurified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA).

²⁾ Reaction conditions: 20 eq. Of methylamine [40% strength aqueous solution]; 7h at 60 ° C.

Example 60A Enantio- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester (mirror isomer A)

100 mg of racemic- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester (Example 55A) was separated on the palm phase into mirror image isomers [ Column: Daicel Chiralpak AY-H, 5μm, 250 x 20mm, mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine, flow rate 15ml / min; 30 ° C, detection: 220nm].

Yield: 43 mg of mirror isomer A (99% purity,> 99% ee)

R _t = 4.58min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 61A Enantiomer- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester (mirror isomer B):

100 mg of racemic- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester (Example 55A) was separated on the palm phase into mirror image isomers [ Column: Daicel Chiralpak AY-H, 5μm, 250 x 20mm, mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine, flow rate 15ml / min; 30 ° C, detection: 220nm].

Yield: 44 mg of mirror image isomer B (99% purity,> 99% ee) R _t = 5.61min [Daicel Chiralpak AY-H, 5 μm, 250 x 4.6mm; mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 62A Enantio- [2-amino-2- (2,4-difluorophenyl) ethyl] carbamic acid tert-butyl ester (mirror isomer A)

435 mg of Example 59A was separated into mirror image isomers on the opposite palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine, Flow rate 15ml / min; 30 ° C, detection: 220nm]. Remove residual solvent, The product was dissolved in acetonitrile / water and lyophilized.

Yield: 182mg (97% purity,> 99% ee)

Mirror isomer B: R _t = 5.25min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ℃; detection: 220nm].

Example 63A Enantio- [1- (3,4-difluorophenyl) ethane-1,2-diyl] diamino benzyl tertiary butyl ester

300 mg of enantio- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid tert-butyl ester (mirromeric isomer A) (Example 60A; 1.10 mmol) was placed first 5 ml of anhydrous THF, and then dropwise add 1.15 ml of diisopropylethylamine (6.6 mmol, 6 eq.), 26 mg of N, N-dimethylaminopyridine (0.22 mmol, 0.2 eq.), 0.31 ml of benzyl chloroformate (2.2 mmol, 2 equivalents). The reaction mixture was stirred at RT for 48 h, then concentrated, treated in ethyl acetate and washed with water. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). This gave 336 mg (75% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.14min

MS (ES +): m / z = 407.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.3 (s, 9 H); 3.13 (t, 2 H); 4.65 (q, 1 H); 5.00 (q, 2 H); 6.88 (t, 1 H); 7.1 (br.s., 1 H); 7.21-7.40 (m, 7 H); 7.80 (d, 1 H).

Example 64A Enantio- [2-amino-1- (3,4-difluorophenyl) ethyl] carbamic acid benzyl ester

16.5 ml of a 2N solution of hydrochloric acid in ether was added to 335 mg of enantio- [1- (3,4-difluorophenyl) ethane-1,2-diyl] diamino benzyl tertiary butyl ester ( Example 63A; 0.824 mmol), and the mixture was stirred at RT overnight. Add another 16.5ml of 4N HCl Alkane solution, and the mixture was stirred at RT for another 3 h. The reaction mixture was concentrated, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 252.4 mg (84% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 307.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.82-1.95 (br.s, 2 H); 2.70 (d, 2 H); 4.49 (q, 1 H); 5.00 (m, 2 H); 7.1 (br.s., 1 H); 7.21-7.40 (m, 7 H); 7.80 (d, 1 H).

Example 65A Racemic- (3-ethoxy-2-hydroxypropyl) carbamic acid third butyl ester

3 g of racemic-1-amino-3-ethoxy-2-propanol hydrochloride (19.28 mmol, 1 equivalent) was first placed in 40 ml of dichloromethane, and 5.7 ml of triethylamine was added (40.9 mmol, 2.1 equivalents) and then 4.96 ml of di-t-butyl dicarbonate (21.6 mmol, 1.12 equivalents). The reaction mixture was stirred at RT for 2 h, diluted with dichloromethane and saturated aqueous sodium bicarbonate solution and saturated Wash with an aqueous solution of sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was dried under high vacuum. This gave 3.73 g of crude product (88% of theory), which was further reacted without any subsequent treatment.

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.10 (t, 3H); 1.39 (s, 9 H); 2.85 (dt, 1 H); 3.02 (dt, 1 H); 3.20-3.30 (m , 2 H); 3.40 (q, 2 H); 3.55-3.60 (m, 1 H); 4.75 (d, 1 H); 6.61 (t, 1 H).

Example 66A Racemic- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-ethoxypropyl] aminoformic acid third butyl ester

At RT, 3.73 g of racemic- (3-ethoxy-2-hydroxypropyl) carbamic acid third butyl ester (17 mmol, 1 equivalent) and 2.50 g of phthalimidine imine (17 mmol, 1 equivalent) And 6.69 g of triphenylphosphine (25.52 mmol, 1.5 equivalents) were first placed in 70 ml of anhydrous THF. 5.06 ml of diisopropyl azodicarboxylate (25.5 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was diluted to 90 ml with methanol, acetonitrile, and water and purified by preparative HPLC (column material: Sunfire C18 5 μm 75x30 mm; flow rate 56 ml / min; mobile phase: 45% Milli-Q-water / 50% acetonitrile / 5% 1% formic acid aqueous solution; injection volume: 0.5 ml; detection wavelength: 210 nm). This gave 4.88 g of the title compound (82% of theory).

LC-MS (Method 2): R _t = 1.04min

MS (ES +): m / z = 349.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.02 (t, 3H); 1.25 (s, 9 H); 3.34-3.48 (m, 4 H); 3.65 (dd, 1 H); 3.81 (dd , 1 H); 4.32-4.38 (m, 1 H); 7.10 (t, 1 H); 7.80- 7.90 (m, 4 H).

Example 67A Racemic- (2-amino-3-ethoxypropyl) carbamic acid third butyl ester

4.88 g of racemic- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-ethoxypropyl] carbamic acid Tributyl ester (14.0 mmol, 1 equivalent) was first put into 12 ml of a 40% strength methylamine aqueous solution and reacted in a microwave at 100 ° C for 1.5 h. The reaction mixture was concentrated, the residue was treated in 10 ml of toluene and concentrated again. Repeat this step several times. The residue was then chromatographed on silica gel (mobile phase: dichloromethane / methanol 10: 1). This gave 470 mg (15% of theory) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.10 (t, 3H); 1.38 (s, 9 H); 3.03-3.20 (m, 3 H); 3.34-3.48 (m, 4 H); 6.95 (t, 1 H).

Example 68A Racemic- (2-hydroxy-3-phenoxypropyl) carbamic acid third butyl ester

1.13 g of racemic-1-amino-3-phenoxyprop-2-ol hydrochloride (5.5 mmol, 1 equivalent) was first put into 11.5 ml of dichloromethane, and 1.64 ml of tris Ethylamine (11.7 mmol, 2.1 equivalents) and then 1.43 ml of di-t-butyl dicarbonate (6.21 mmol, 1.12 equivalents). The reaction mixture was stirred at RT for 2 h, diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was dried under high vacuum to obtain 1.5 g of a crude product (quantitative yield), which was further reacted without further purification.

LC-MS (Method 2): R _t = 0.88min

MS (ES +): m / z = 268.2 (M + H) ⁺

Example 69A Racemic- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-phenoxypropyl] aminocarboxylic acid third butyl ester

At RT, 1.5 g of racemic- (2-hydroxy-3-phenoxypropyl) carbamic acid third butyl ester (5.6 mmol, 1 equivalent) and 0.99 g of phthaloimine (6.73 mmol, 1.2 Equivalent) and 2.21 g of triphenylphosphine (8.4 mmol, 1.5 equivalents) were first placed in 23 ml of anhydrous tetrahydrofuran. 1.70 ml of diisopropyl azodicarboxylate (8.4 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. LC / MS showed complete conversion of the reaction. The reaction mixture was concentrated and purified by chromatography on silica gel (Biotage Isolera; cyclohexane / ethyl acetate gradient as mobile phase). This gave 1.08 g of the title compound (48% of theory).

LC-MS (Method 2): R _t = 1.13min

MS (ES +): m / z = 397.3 (M + H) ⁺

Example 70A Racemic- (2-amino-3-phenoxypropyl) carbamic acid third butyl ester

1.08 g of racemic- [2- (1,3-dioxo-1,3-dihydro-2H-isoindole-2- (Phenyl) -3-phenoxypropyl] carbamic acid third butyl ester (2.72 mmol, 1 equivalent) was first put into 5 ml of a 40% strength methylamine aqueous solution and reacted in a microwave at 100 ° C for 2 h. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane / methanol gradient). This gave 200 mg (27% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.57min

MS (ES +): m / z = 267.1 (M + H) ⁺

Example 71A Racemic- [3- (4-fluorophenoxy) -2-hydroxypropyl] carbamic acid third butyl ester

0.93 g of racemic-1-amino-3- (4-fluorophenoxy) propan-2-ol (5.07 mmol, 1 equivalent) was first placed in 10.5 ml of dichloromethane, and 1.5 was first added ml of triethylamine (10.7 mmol, 2.1 equivalents) and then 1.31 ml of di-t-butyl dicarbonate (5.68 mmol, 1.12 equivalents). The reaction mixture was stirred at RT for 2h. The mixture was then diluted with dichloromethane and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was used in the next reaction without further purification.

LC-MS (Method 2): R _t = 0.89min

MS (ES +): m / z = 286.2 (M + H) ⁺

Example 72A Racemic- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -3- (4-fluorophenoxy) propyl] carbamic acid Tert-butyl ester

At RT, 1.5 g of racemic- [3- (4-fluorophenoxy) -2-hydroxypropyl] carbamic acid third butyl ester (5.26 mmol, 1 equivalent) and 0.93 g of phthalimidine (6.31 mmol, 1.2 equivalents) and 2.07 g of triphenylphosphine (7.9 mmol, 1.5 equivalents) were first placed in 22 ml of anhydrous THF. 1.56 ml of diisopropyl azodicarboxylate (7.9 mmol, 1.5 equivalents) was added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (Biotage Isolera; cyclohexane / ethyl acetate gradient as mobile phase). This gave 1.97 g of the title compound (90% of theory).

LC-MS (Method 2): R _t = 1.14min

MS (ES +): m / z = 415.3 (M + H) ⁺

Example 73A Racemic- [2-amino-3- (4-fluorophenoxy) propyl] carbamic acid third butyl ester

1.97 g of racemic- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3- (4-fluorophenoxy) propene The butyl] -carbamic acid third butyl ester (4.75 mmol, 1 equivalent) was first put into 5 ml of a 40% strength methylamine aqueous solution, and the mixture was reacted in a microwave at 100 ° C for 2 h. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane / methanol gradient). This gave 900 mg (67% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 285.1 (M + H) ⁺

Example 74A Racemic- (2-hydroxy-3-isopropoxypropyl) carbamate

1 g of racemic-1-amino-3-isopropoxypropan-2-ol (7.5 mmol, 1 equivalent) was first placed in 25 ml of THF, and 1.16 ml of benzyl chloroformate (8.3 mmol, 1.1 equivalents), 3.9 ml of diisopropylethylamine (22.5 mmol, 3 equivalents), and 183 mg of N, N-dimethylaminopyridine (1.5 mmol, 0.2 equivalents). The reaction mixture was stirred at RT, and after 5 minutes, 5 ml of DMF was added. After another 2.5 h at RT, the mixture was concentrated to dryness. The residue was treated in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was used in the next reaction without further purification.

LC-MS (Method 2): R _t = 0.80min

MS (ES +): m / z = 268.2 (M + H) ⁺

Example 75A Racemic- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-isopropoxypropyl] carbamic acid benzyl ester

At RT, 1.28 g of racemic benzyl (2-hydroxy-3-isopropoxypropyl) carbamate (4.79 mmol, 1 equivalent) and 0.85 g of phthaloimine (5.75 mmol, 1.2 Equivalent) and 1.88 g of triphenylphosphine (7.2 mmol, 1.5 equivalents) were first placed in 20 ml of anhydrous tetrahydrofuran. 1.42 ml of diisopropyl azodicarboxylate (7.2 mmol, 1.5 equivalents) was added dropwise, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel (Biotage Isolera; cyclohexane / ethyl acetate gradient as mobile phase). This gave 2.3 g (66% purity; 78% of theory) of the title compound (incorporated with hydrazine-1,2-carboxylic acid diisopropyl ester).

LC-MS (Method 2): R _t = 1.12min

MS (ES +): m / z = 397.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.91 (d, 3 H), 1.00 (d, 3 H), 3.42-3.48 (m, 2 H), 3.50 (hept, 1 H), 3.69 ( dd, 1 H), 3.79 (t, 1 H), 4.31 (q, 1 H), 4.91 (s, 2 H), 7.20-7.30 (m, 5 H), 7.52 (t, 1 H), 7.80- 7.86 (m, 4 H).

Example 76A Racemic- (2-amino-3-isopropoxypropyl) carbamic acid benzyl ester

2.3 g of racemic- [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -3-isopropoxypropyl] carbamic acid Benzyl ester (5.6 mmol, 1 eq.) Was dissolved in 30 ml of ethanol. 7.3 ml of a 40% strength methylamine aqueous solution (84.4 mmol, 15 equivalents) were added and the mixture was stirred at 60 ° C. overnight. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane / methanol gradient). This gave 730 mg (49% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.59min

MS (ES +): m / z = 267.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (d, 6 H), 1.74 (br.s, 2 H), 2.79-2.90 (m, 2 H), 3.02-3.12 (m, 1 H ), 3.18 (dd, 1 H), 3.21 (dd, 1 H), 3.50 (q, 1 H), 5.00 (s, 2 H), 7.18 (t, 1 H), 7.28-7.39 (m, 5 H ).

Example 77A Racemic- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino ] -2- (3,4-difluorophenyl) ethyl} carbamic acid tert-butyl ester

200 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (0.63 mmol), 242 mg of racemic- (Benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 0.75 mmol) and 318 mg of 4-methylmorpholine (3.14 mmol) were first placed in 4.3 ml of DMF. At RT, 242 mg of racemic- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester (Example 55A, 0.75 mmol) was added, and the mixture was stirred at RT stir Stir until overnight. Approximately 16 ml of water was added to the reaction solution, the mixture was stirred for another 30 min and the formed precipitate was filtered and washed with water. The solid was treated with about 4 ml of acetonitrile in an ultrasonic bath for 10 min, filtered and dried under high vacuum overnight. This gave 355 mg of the title compound (96% of theory).

LC-MS (Method 2): R _t = 1.10min

MS (ES +): m / z = 573 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.32 (s, 9H), 2.59 (s, 3H), 3.29-3.46 (m, 2H), 5.15 (q, 1H), 5.31 (s, 2H) , 6.91 (t, 1H), 7.01 (d, 1H), 7.08 (t, 1H), 7.19-7.27 (m, 3H), 7.36-7.51 (m, 2H), 7.59 (q, 1H), 8.21 (d 1H), 8.56 (d, 1H).

The examples shown in Table 8A were prepared by 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid and Or prepared from commercially available amines (1.1-1.5 equivalents) and 4-methylmorpholine (4-6 equivalents) under the reaction conditions described in General Operation Process 3.

¹⁾ Follow-up: The crude reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA).

²⁾ Post-treatment: the precipitate was purified by silica gel chromatography (mobile phase: dichloromethane: methanol 200: 1).

³⁾ Subsequent processing: The precipitate was purified by silica gel chromatography (mobile phase: cyclohexane: ethyl acetate 2: 1).

Example 106A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] -2- (3,4-difluorophenyl) ethyl} carbamic acid third butyl ester

90 mg of 8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 11A; 0.268 mmol, 1 equivalent), 132 mg of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (0.348 mmol, 1.4 equivalents) and 0.132 ml of N, N-diisopropylethylamine (0.803 mmol, 3 equivalents) were first placed in 0.85 ml of DMF, and 102 mg of enantio- [2-amine was added at RT Tert-butyl 2- (3,4-difluorophenyl) ethyl] carbamate (Example 60A) and the mixture was stirred at RT overnight. Water was added to the reaction solution, the mixture was stirred for another 30 min and the formed precipitate was filtered off and washed with water, a little acetonitrile and methanol. This gave 148 mg (85% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.24min

MS (ES +): m / z = 591.4 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.34 (s, 9H), 2.58 (s, 3H; partly hidden by DMSO signal), 3.35-3.45 (m, 2H; partly overlaps with H ₂ O signal) , 5.15 (q, 1H), 5.31 (s, 2H), 7.10 (t, 1H), 7.19-7.27 (m, 4H), 7.36-7.50 (m, 2H), 7.59 (quint, 1H), 8.21 (d 1H), 8.62 (d, 1H).

The examples shown in Table 9A are representative operations using Examples 3A, 16A, 21A, 25A, and 28A with suitable amines and N, N-diisopropylethylamine, either commercially available or prepared according to the described methods, Prepared by reacting under the reaction conditions described in Process 3.

Example 118A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] 2- (3,4-difluorophenyl) ethyl} carbamate tert-butyl ester

1.50 g of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine 3-carboxylic acid (4.71 mmol), 1.67 g of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 5.18 mmol) and 2.38 g of 4-formaldehyde The morpholine (23.5 mmol) was first placed in 30 ml of DMF. At RT, 1.48 g of enantio- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid third butyl ester (Example 60A, 5.42 mmol) was added and the mixture was stirred at RT 2h. The reaction mixture was poured into about 250 ml of water and the precipitated solid was stirred at RT for about 30 min. The solid was then filtered off, washed with water and subsequently dried under high vacuum. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol = 100/1). This gave 2.18 g of the title compound (81% of theory).

LC-MS (Method 2): R _t = 1.12min

MS (ES +): m / z = 573 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.32 (s, 9H), 2.59 (s, 3H), 3.29-3.46 (m, 2H), 5.15 (q, 1H), 5.31 (s, 2H) , 6.91 (t, 1H), 7.01 (d, 1H), 7.08 (t, 1H), 7.19-7.27 (m, 3H), 7.36-7.51 (m, 2H), 7.59 (quint, 1H), 8.21 (d 1H), 8.56 (d, 1H).

Example 119A Enantiomer- {2-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] propyl} carbamic acid third butyl ester (mirromeric isomer A)

227 mg of Example 87A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol, flow rate 20 ml / min; 25 ℃, detection: 230nm].

Yield of isomer A: 74 mg (> 99% ee)

Mirror isomer A: R _t = 4.66min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate: 1.0ml / min; 25 ° C; detection: 230nm].

Example 120A Enantiomer- {2-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] propyl} benzyl carbamate (mirror isomer B)

227 mg of Example 87A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol, flow rate 20 ml / min; 25 ℃, detection: 230nm].

Yield of mirror image isomer B: 58mg (> 99% ee)

Mirror isomer B: R _t = 5.90min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 25 ° C; detection: 230nm ].

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.13 (d, 3H), 1.37 (s, 9H), 2.50 (s, 3H), 3.05-3.19 (m, 2H), 4.05-4.17 (m, 1H), 5.33 (s, 2H), 6.95 (t, 1H), 7.19 (s, 1H), 7.22 (t, 2H), 7.60 (quintet, 1H), 7.68 (d, 1H), 8.71 (s , 1H).

Example 121A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amino] propyl} carbamic acid third butyl ester (mirromeric isomer A)

215 mg of Example 88A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 30 ° C, detection: 220nm].

Mirror isomer A (still containing impurities) was dissolved in 0.5 ml of methanol and 2.5 ml of third butyl methyl ether and repurified [column: Daicel Chiralpak IA, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane , 30% ethanol + 0.2% diethylamine, flow rate 25ml / min; 25 ° C, detection: 220nm].

Yield of mirror image isomer A: 48mg (> 99% ee)

Mirror isomer A: R _t = 7.48min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ℃; detection: 220nm].

Example 122A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] propyl} carbamic acid third butyl ester (mirromeric isomer B)

215 mg of Example 88A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 30 ° C, detection: 220nm].

Yield of mirror image isomer B: 67mg (> 99% ee)

Mirror isomer B: 11.28min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection Measurement: 220nm].

Example 123A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-ethoxypropyl} third carbamate (mirromeric isomer A)

211 mg of Example 110A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethyl acetate Alcohol, flow rate: 15 ml / min; 30 ° C, detection: 220 nm].

Yield of isomer A: 84 mg (99% ee)

Mirror isomer A: R _t = 7.56min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 124A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-ethoxypropyl} third carbamate (mirromeric isomer B)

211 mg of Example 110A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 15 ml / min; 30 ° C, detection: 220nm].

Yield of isomer B: 82 mg (99% ee)

Mirror isomer B: R _t = 9.71min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 125A Enantiomer- {2-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] -3-ethoxypropyl} carbamic acid tert-butyl ester (mirror isomer A)

270mg of Example 111A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 15ml / min; 30 ° C, detection: 220nm].

Yield of mirror image isomer: 114mg (99% ee)

Mirror isomer A: R _t = 4.66min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 30 ° C; detection : 220nm].

Example 126A Enantiomer- {2-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] -3-ethoxypropyl} carbamic acid third butyl ester (mirror isomer B)

270 mg of Example 111A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 15ml / min; 30 ° C, detection: 220nm].

Yield of image isomer B: 118 mg (99% ee)

Mirror isomer B: R _t = 6.75min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 127A 3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -9-nitrogen Heterobicyclo [3.3.1] nonane-9-carboxylic acid tert-butyl trifluoroacetate

400 mg (1.07 mmol) of (8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carbonyl chloride hydrochloride (Example 22A ) First put in 40 ml of anhydrous THF. Then add 309 mg (1.29 mmol) of 3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylic acid third butyl ester and 554 mg (4.29 mmol ) N, N-diisopropylethylamine, and the mixture was stirred at RT for 1 h. The reaction solution was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). This gave 620 mg of the title compound (88% of theory).

LC-MS (Method 2): R _t = 1.07min

MS (ES +): m / z = 541 (M-TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.40 (s, 9H), 1.62-1.79 (m, 7H), 1.81-2.06 (m, 3H), 2.50 (s, 3H), 4.22 (d, 2H), 4.78-4.90 (m, 1H), 5.40 (s, 2H), 7.25 (t, 3H), 7.41 (br s, 1H), 7.60 (quint, 1H), 8.09 (br s, 1H), 8.63 (d, 1H).

Example 128A 8-[(2,6-difluorobenzyl) oxy] -N-[(2R) -1-hydroxyhex-2-yl] -2-methylimidazo [1,2-a] pyridine-3 -Carboxamide

2 g of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 3A, 6.28 mmol, 1 equivalent), 2.2 g of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU; 6.9 mmol, 1.1 equivalents) and 3.45 ml of 4-methylmorpholine (31.4 mmol , 5 equivalent) was first placed in 15 ml of dichloromethane and 10 ml of DMF. At RT, 1.810 mg of (R)-(-)-2-amino-1-hexanol (6.9 mmol, 1.1 equivalents) was added and the mixture was stirred for 3 h. The mixture was then diluted with dichloromethane and adjusted to pH 4 with water and a 1N aqueous hydrochloric acid solution. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed twice with water, dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by preparative HPLC (Method 9). This gave 1,066 mg (41% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.87min

MS (ES +): m / z = 418.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 1.23-1.70 (m, 6H), 2.54 (s, 3H), 3.39-3.54 (m, 2H), 3.92-4.02 ( m, 1H), 4.74 (t, 1H), 5.31 (s, 2H), 6.92 (t, 1H), 6.99 (d, 1H), 7.23 (t, 2H), 7.52 (d, 1H), 7.59 (m , 1H), 8.53 (d, 1H).

Example 129A 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N-[(2R) -1-oxohex-2-yl] imidazo [1,2-a] pyridine- 3- Carboxamide

1.14 g of Dess-Martin periodinane (2.7 mmol, 1.5 equivalents) was first placed in 25 ml of dichloromethane, and 0.145 ml of pyridine (1.8 mmol, 1 Equivalent) and 750 mg of 8-[(2,6-difluorobenzyl) oxy] -N-[(2R) -1-hydroxyhex-2-yl] -2-methylimidazo [1,2- a] Pyridine-3-carboxamide (Example 3A, 1.8 mmol). The reaction mixture was stirred at this temperature for 2 h. A 1N aqueous sodium hydroxide solution was added under ice-cooling, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 899 mg (about 70% purity; 90% of theory) of the target compound, which was not further purified.

LC-MS (Method 2): R _t = 1.00min [hydrate: 0.83min]

MS (ES +): m / z = 416.3 (M + H) ⁺ [hydrate: 434.3 (M + H ⁺ )]

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 1.20-1.95 (m, 6H), 2.54 (s, 3H), 4.30-4.38 (m, 1H), 5.31 (s, 2H), 6.92 (t, 1H), 7.01 (d, 1H), 7.23 (t, 2H), 7.59 (m, 1H), 8.20 (d, 1 H), 8.57 (d, 1H), 9.10 (s, 1 H).

Example 130A Enantiomer- [2-({[8- (benzyloxy) -2-methylimidazo [1,2-a] pyridin-3-yl] carbonyl} amino) -2- (3,4-di Fluorophenyl) ethyl] carbamic acid tert-butyl ester

Enantiomer- [2-amino-2- (3,4-difluorophenyl) ethyl] carbamic acid tert-butyl ester (starter 60A, 19.96 mmol, 1.15 equivalents) was added to 4.90 g of 8- ( Benzyloxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 30A, 17.36 mmol, 1 equivalent), 6.13 g of (benzotriazol-1-yloxy) A solution of bisdimethylaminomethylium fluoroborate (TBTU, 19 mmol, 1.1 equivalents) and 9.5 ml of N-methylmorpholine (8.78 g, 86.8 mmol, 5 equivalents) in 110 ml of DMF. The reaction mixture was stirred at room temperature for 2 h, then poured into 800 ml of water and extracted with 800 ml and 300 ml of ethyl acetate. The organic phase was washed with 300 ml of a saturated aqueous sodium chloride solution, dried and concentrated to about 15 ml. The residue was triturated with 90 ml of tert-butyl methyl ether, filtered, washed with 30 ml of tert-butyl methyl ether and then with n-pentane and dried under reduced pressure. This gave 7.30 g (75% of theory) of the title compound.

LC-MS (Method 7): R _t = 1.06min

MS (ES +): m / z = 537.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = ppm 1.33 (s, 9 H), 2.61 (s, 3 H), 5.11-5.21 (m, 1 H), 5.28 (s, 2 H), 6.84 -6.95 (m, 2 H), 7.08 (t, 1 H), 7.21-7.28 (m, 1 H), 7.43 (m, 7 H), 8.20 (d, 2 H), 8.52 (d, 2 H) .

Example 131A Enantiomer- [2- (3,4-difluorophenyl) -2-{[((8-hydroxy-2-methylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino} Ethyl] carbamate

6.90 g of enantiomer- [2-({[8- (benzyloxy) -2-methylimidazo [1,2-a] pyridin-3-yl] carbonyl} amino) -2- (3 , 4-Difluorophenyl) ethyl] carbamic acid third butyl ester (Example 130A, 12.8 mmol, 1 equivalent) was first put into 207 ml of a 1: 1 ethanol / THF / dichloromethane mixture and 0.69 g 10% activated carbon on palladium. The mixture was hydrogenated at RT and standard hydrogen pressure overnight. 500 ml of dichloromethane were then added and the reaction mixture was filtered through silica gel at 40 ° C, washed with dichloromethane and dried under reduced pressure. This gave 5.20 g (83% of theory; purity 92%) of the title compound.

LC-MS (Method 2): R _t = 0.84min

MS (ES +): m / z = 447.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.33 (s, 9 H), 2.63 (s, 3 H), 5.10-5.22 (m, 1 H), 6.65 (d, 1 H), 6.80 ( t, 1 H), 7.08 (t, 1 H), 7.20-7.27 (m, 1 H), 7.36-7.54 (m, 2 H), 8.18 (d, 1 H), 8.43 (d, 1 H), [Also the signal is hidden under the solvent peak].

Example 132A Racemic- (2-hydroxy-3-methoxypropyl) carbamate

5.0 g (47.6 mmol) of racemic-1-amino-3-methoxyprop-2-ol was placed in advance THF (158 ml), and 7.36 ml (52.3 mmol) of benzyl chlorocarbonate, 24.85 ml (142.7 mmol) of N, N-diisopropylethylamine and 1.16 g (9.5 mmol) of 4- Dimethylaminopyridine. The reaction mixture was stirred at RT for 16 h. 3.7 ml (26.2 mmol) of benzyl chlorocarbonate and then 15 ml of DMF were added, and the reaction solution was stirred at RT overnight. The mixture was concentrated and diluted with ethyl acetate. The mixture was then washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The aqueous phase was concentrated, the residue was taken up in ethyl acetate, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The two fractions were combined and purified by silica gel chromatography (dichloromethane / methanol gradient: from 100: 0 to 10: 1). This gave 12.16 g (81% of theory, 76% purity) of the target compound.

LC-MS (Method 7): R _t = 0.68min

MS (ESI +): m / z = 240 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.90-2.98 (m, 1H), 3.03-3.11 (m, 1H), 3.18-3.28 (m, 5H), 3.58-3.66 (m, 1H), 4.85 (d, 1H), 5.01 (s, 2H), 7.17 (t, 1H), 7.28-7.40 (m, 5H).

Example 133A [(2S) -3-hydroxybut-2-yl] benzyl carbamate

Under argon, 810 mg of [(2S) -3-oxobut-2-yl] carbamic acid benzyl ester (Example 150A, 3.7 mmol, 1 equivalent) was first placed in 12 ml of anhydrous THF and 12 ml of methanol. 208 mg of sodium borohydride (5.5 mmol, 1.5 equivalents) were added at 0 ° C. After 2 h at 0 ° C, the mixture was concentrated, water and saturated aqueous sodium bicarbonate solution were added to the residue and the mixture was extracted four times with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. This gave 777 mg (90% of theory) of the title compound.

Diastereomeric mixture ratio 2: 1

Major diastereomers: LC-MS (Method 2): Rt = 0.78min

MS (ES +): m / z = 224.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.01 (m, 6 H), 3.43-3.51 (m, 1 H), 4.48 (d, 1 H), 5.00 (s, 2 H), 7.34- 7.38 (m, 5 H), [Other signals are hidden under the solvent peak].

Example 134A [(2R) -3-hydroxybut-2-yl] carbamic acid benzyl ester

Under argon, place 885 mg of [(2R) -3-oxobut-2-yl] carbamic acid benzyl ester (Example 151A, 4 mmol, 1 equivalent) into 13 ml of THF and 13 ml of methanol, and Similar Example 133A was reacted with 227 mg of sodium borohydride (6 mmol, 1.5 equivalents) and subsequently processed. This gave 830 mg (92% of theory) of the title compound.

Diastereomeric mixture ratio 2: 1

Major diastereomers: LC-MS (Method 2): R _t = 0.78min

MS (ES +): m / z = 224.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.01 (m, 6 H), 3.43-3.51 (m, 1 H), 4.48 (d, 1 H), 5.00 (s, 2 H), 7.34- 7.38 (m, 5 H), [Other signals are hidden under the solvent peak].

Example 135A Racemic- [3- (3,4-difluorophenoxy) -2-hydroxypropyl] carbamic acid benzyl ester

1 g of racemic-1-amino-3- (3,4-difluorophenoxy) propan-2-ol (4.9 mmol, 1 equivalent) was dissolved in 16 ml of THF, and 0.76 ml of chloroformic acid was added. Benzyl ester (0.9 g, 5.4 mmol, 1.1 eq) and then 2.6 ml of N, N-diisopropylethylamine (1.9 g, 14.8 mmol, 3 eq) and 0.12 g of 4-dimethylamino Pyridine. The mixture was stirred at RT for 30 min. Then 2 ml of DMF was added and the mixture was stirred at RT overnight. The mixture was concentrated and the residue was then worked up in ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. This gave 2.2 g (96% of theory, 73% purity) as the crude product, which was reacted without further purification.

LC-MS (Method 2): Rt = 1.00min

MS (ES +): m / z = 338.2 (M + H) ⁺

Example 136A Racemic- [2- (1,3-Dioxo-1,3-dihydro-2H-isoindole-2-yl) -3-methoxypropyl] carbamic acid benzyl ester

12.10 g (38.4 mmol, 76%) of racemic- (2-hydroxy-3-methoxypropyl) carbamic acid benzyl ester (Example 132A), 6.79 g (46.1 mmol) of 1H-isoindole- 1,3 (2H) -dione and 15.12 g (57.7 mmol) of triphenylphosphine was first placed in THF (158 ml). 11.4 ml (57.7 mmol) of diisopropyl azodicarboxylate were added dropwise and the mixture was then stirred at RT for 10 min. The mixture was then concentrated and the residue was purified by silica gel chromatography (cyclohexane / ethyl acetate gradient: from 3: 0 to 2: 1). The product was concentrated and the fractions were concentrated. This gave 14.84 g (97% of theory, 93% purity) of the target compound.

LC-MS (Method 2): R _t = 0.95min.

MS (ESIpos): m / z = 369 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.22 (s, 3H), 3.46 (t, 2H), 3.63 (dd, 1H), 3.80 (t, 1H), 4.37-4.47 (m, 1H) , 4.94-4.98 (m, 2H), 7.20-7.35 (m, 5H), 7.56 (t, 1H), 7.81-7.90 (m, 4H).

Example 137A [(2S) -3- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) but-2-yl] carbamic acid benzyl ester

Under argon, 0.72 g of [(2S) -3-hydroxybut-2-yl] carbamic acid benzyl ester (Example 133A, 3.3 mmol, 1 equivalent), 0.57 g of 1H-isoindole-1, 3 (2H) -dione (3.9 mmol, 1.2 equivalents) and 1.3 g of triphenylphosphine (4.9 mmol, 1.5 equivalents) were dissolved in 15 ml of THF, and 1.1 g of (E) -diazene- Di-tert-butyl 1,2-dicarboxylic acid (DIAD, 4.9 mmol, 1.5 equivalents). The mixture was stirred until overnight at RT, was added 2 drops of water and the mixture was concentrated and the Extrelut ^®. The residue was purified on a silica gel filter (Biotage SNAP Cartridge KP-Sil 25g) (gradient cyclohexane / ethyl acetate from 5% to 100%). The resulting crude product was left in a mixture of 5 ml of methanol and 1 ml of water overnight. The obtained solid was filtered off, washed with a little methanol / water mixture and dried under reduced pressure. The filtrate was purified by preparative HPLC (Method 9). This gave a total of 692 mg (53% of theory, 87% purity) of the title compound (diastereomeric mixture ratio of about 4: 1).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 353.2 (M + H) ⁺

Example 138A [(2R) -3- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) but-2-yl] carbamic acid benzyl ester

Under argon, similar to Example 137A, 0.82 g of [(2R) -3-hydroxybut-2-yl] carbamic acid benzyl ester (Example 134A, 3.3 mmol, 1 equivalent) and 0.57 g of 1H-isoindole -1,3 (2H) -diketone (peptidimidine, 3.9 mmol, 1.1 equivalents) was reacted and subsequently processed. This gave 1.25 g (72% of theory; 75% purity) of the title compound (diastereomer ratio of about 3: 1).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 353.2 (M + H) ⁺

Example 139A Racemic- [3- (3,4-difluorophenoxy) -2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) propyl ] Benzyl carbamate

Similarly to Example 137A, 2.2 g of racemic- [3- (3,4-difluorophenoxy) -2-hydroxypropyl] carbamic acid benzyl ester (Example 135A, 6.5 mmol, 1 equivalent) and 1.2 g 1H-isoindole-1,3 (2H) -diketone (phthalimide, 7.8 mmol, 1.2 equivalents) and subsequent treatment. This gave 1.78 g (54% of theory; purity 93%) of the title compound.

LC-MS (Method 2): R _t = 1.17min

MS (ES +): m / z = 467.2 (M + H) ⁺

Example 140A Racemic- (2-amino-3-methoxypropyl) benzyl carbamate trifluoroacetate

Add 123 ml (1.43 mol) of methylamine (40% aqueous solution) to 14.13 g (35.7 mmol, 93% purity) of racemic- [2- (1,3-dioxo-1,3-di Hydrogen-2H-isoindol-2-yl) -3-methoxypropyl] carbamic acid benzyl ester (Example 136A). The reaction mixture was stirred in a closed container at 60 ° C for 35 min. The mixture was then concentrated and treated three times in methanol and reconcentrated, and the residue was purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was isolated and still contained impurities and purified by RP-HPLC (acetonitrile / water gradient with 0.1% TFA). This gave 9.7 g (69.5% of theory, 90% purity) of the target compound.

LC-MS (Method 7): R _t = 0.46min.

MS (ESIpos): m / z = 239 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.18-3.58 (m, 8H, overlapping with water signal), 5.05 (s, 2H), 7.29-7.40 (m, 5H), 7.48 (t, 1H) , 7.82-8.01 (br.s, 2H).

Example 141A [(2S) -3-Aminobut-2-yl] benzyl carbamate

600 mg of [(2S) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) but-2-yl] carbamic acid benzyl ester (Example 137A, 1.7 mmol, 1 equivalent) was suspended in 10 ml of methanol, and 2.9 ml of a 40% strength methylamine aqueous solution (2.6 g, 34 mmol, 20 equivalents) was added at RT. The mixture was placed overnight at RT and to Extrelut ^® and the mixture was then added to the concentrate. The residue was purified on a silica gel filter (Biotage Isolera SNAP Cartridge KP-Sil 25g, mobile phase: dichloromethane / methanol from 95: 5 to 0: 100). This gave 293 mg (43% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.49min

MS (ES +): m / z = 223.2 (M + H) ⁺

Example 142A [(2R) -3-Aminobut-2-yl] carbamic acid benzyl ester

Similar to Example 141A, 1.2 g of [(2R) -3- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) but-2-yl] aminocarboxylic acid The benzyl ester (Example 138A, 3.4 mmol, 1 equivalent) was reacted and subsequently worked up. The obtained crude product was subjected to silica gel chromatography, and then purified by preparative HPLC (Method 9). This gave 147 mg (19% of theory) of the title compound (diastereomeric ratio of about 3: 1).

LC-MS (Method 2): R _t = 0.48min

MS (ES +): m / z = 223.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.90 (d, 3 H), 0.99 (d, 3 H), 1.4 (br.s, 2 H); 2.63-2.80 (m, 1 H), 3.30-3.40 (m, 1 H; partly overlaps with water signal); 5.01 (s, 2 H), 6.95 (d, 1 H), 7.25-7.44 (m, 5 H).

Example 143A Racemic- [2-amino-3- (3,4-difluorophenoxy) propyl] carbamic acid benzyl ester

1.8 g of racemic- [3- (3,4-difluorophenoxy) -2- (1,3-dioxo-1,3-dihydro-2H-isoindole-2- Propyl] propyl] -carbamic acid benzyl ester (Example 139A) was dissolved in 25 ml of ethanol, 4.8 ml of a 40% strength methylamine aqueous solution (56 mmol, 15 equivalents) were added and the mixture was stirred at 60 ° C. for 4.5 h. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane / methanol gradient). This gave 600 mg (45% of theory; purity 93%) of the title compound.

LC-MS (Method 2): R _t = 0.66min

MS (ES +): m / z = 337.2 (M + H) ⁺

Starter 144A Racemic-2-amino-4,4,4-trifluorobut-1-ol

12.9 ml of a 2M solution of lithium borohydride in THF (25.8 mmol, 2.5 equivalents) was first placed in 20 ml of THF, 6.5 ml of trimethylchlorosilane (51.1 mmol, 5 equivalent) was added and the mixture was stirred at RT for 5 min. Then, 2.0 g of racemic-2-amino-4,4,4-trifluorobutyrate (10.3 mmol, 1 equivalent) was added in small portions at each time, and the mixture was stirred at RT overnight. Then 20.4 ml of methanol was added dropwise, and the mixture was concentrated after the addition was completed. 12 ml of a 20% strength potassium hydroxide aqueous solution was added to the residue, and the mixture was extracted three times with dichloromethane. will The combined organic solution was dried over sodium sulfate, filtered and concentrated. This gave 1.58 g (96% of theory; 90% purity) of the title compound.

MS (Method 10): m / z = 144.0 (M + H) +

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.54 (br.s, 2 H), 1.97-2.15 (m, 1 H), 2.28-2.45 (m, 1 H), 2.84-2.98 (m, 1 H), 3.24 (d, 2 H), 4.78 (br.s, 1 H).

Starting material 145A Racemic- (4,4,4-trifluoro-1-hydroxybut-2-yl) carbamic acid benzyl ester

At RT, 0.38 ml of a 50% strength potassium carbonate aqueous solution (1.7 mmol, 0.68 equivalent) and 0.54 ml of benzyl chloroformate (3.8 mmol, 1.5 equivalent) were added to 400 mg of racemic-2-amino-4. 36 ml of 1,4-di, 4,4,4-trifluorobut-1-ol (Example 144A, 2.5 mmol, about 90% purity, 1 equivalent) In alkane solution, and the mixture was stirred at RT for 2h. Then, 0.11 ml of benzyl chloroformate (0.76 mmol, 0.3 equivalent) and 0.08 ml of a 50% strength potassium carbonate aqueous solution (0.35 mmol, 0.14 equivalent) were further added, and the mixture was stirred at RT for another 30 min. After concentration under reduced pressure, the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The resulting crude product was treated in ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 490 mg (70% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.81min

MS (ES +): m / z = 278.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.20-2.38 (m, 1 H), 3.19-3.27 (m, 1 H), 3.28-3.42 (m, 2 H), 3.72-3.83 (m, 1 H), 4.96-5.08 (m, 3 H), 7.26-7.39 (m, 5 H).

Starter 146A Racemic- [1- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -4,4,4-trifluorobut-2-yl] amine Benzyl formate

Under argon, 1.58 g of racemic- (4,4,4-trifluoro-1-hydroxybut-2-yl) carbamic acid benzyl ester (Example 145A, 5.70 mmol, 1 equivalent), 0.84 g 1H-isoindole-1,3 (2H) -dione (phthalimide, 5.70 mmol, 1 equivalent) and 2.24 g of triphenylphosphine (8.54 mmol, 1.5 equivalents) were dissolved in 28 ml of THF, And at RT, 1.84 g of (E) -diazene-1,2-dicarbonate di-third butyl ester (DIAD, 8.54 mmol, 1.5 equivalents) was added. The mixture was stirred at RT for 30 min and then a water / acetonitrile mixture was added. Purification by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA) gave 1.92 g (79% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.08min

MS (ES +): m / z = 407.2 (M + H) ⁺

Starter 147A Racemic- (1-amino-4,4,4-trifluorobut-2-yl) carbamic acid benzyl ester trifluoroacetate

1.86 g of racemic- [1- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -4,4,4-trifluorobut-2 -Yl] benzyl carbamate (Example 146A, 4.35 mmol, 1 equivalent) dissolved in 15.0 in a 40% strength methylamine aqueous solution (174 mmol, 40 equivalents) and stirred in a sealed flask at 60 ° C. for 30 min. The reaction mixture was concentrated and the residue was then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 1.25 g (74% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 277.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.57-2.71 (m, 1 H), 2.76-2.89 (m, 1 H), 2.93-3.04 (m, 1 H), 4.00-4.14 (m, 1 H), 5.02 (d, 1 H), 5.09 (d, 1 H), 7.27-7.42 (m, 5 H), 7.47-7.53 (m, 1 H), 7.88-8.08 (br.s, 3 H ), [Another signal is hidden behind the DMSO peak].

Example 148A Enantiomer-{(2S) -1- [methoxy (methyl) amino] -1-benzyloxypropan-2-yl} carbamate

Under argon, 2 g of N-[(benzyloxy) carbonyl] -L-alanine (9 mmol, 1 equivalent) was dissolved in 30 ml of THF, and 1.9 g (11 mmol, 1.2 equivalent) of 2-chloro- 4,6-dimethoxy-1,3,5-tri After 3 ml of 4-methylmorpholine (2.7 g, 27 mmol, 3 eq.), The mixture was stirred at RT for 1 h. 0.96 g (9.8 mmol, 1.1 equivalents) of N, O-dimethylhydroxylamine hydrochloride was added and the mixture was stirred at RT overnight. The mixture was then concentrated, ethyl acetate was added to the residue, and the mixture was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated, and the residue was reduced under reduced pressure. Under dry. This gave 2.25 g (61% of theory; 65% purity) of the title compound.

LC-MS (Method 7): R _t = 0.82min

MS (ES +): m / z = 267.1 (M + H) ⁺

Example 149A Enantiomer-{(2R) -1- [methoxy (methyl) amino] -1-benzyloxypropan-2-yl} carbamate

Under argon, 2 g of N-[(benzyloxy) carbonyl] -D-alanine (9 mmol, 1 equivalent) was dissolved in 30 ml of THF, and 1.9 g (11 mmol, 1.2 equivalent) of 2-chloro-4 was added. , 6-dimethoxy-1,3,5-tri And 3 ml of 4-methylmorpholine (2.7 g, 27 mmol, 3 eq) and 0.96 g (9.8 mmol, 1.1 eq) of N, O-dimethylhydroxylamine hydrochloride, the mixture was stirred at RT to Overnight. The mixture was then concentrated, ethyl acetate was added to the residue, and the mixture was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated, and the residue was under reduced pressure. dry. This gave 2.11 g (64% of theory; 61% purity) of the title compound as a colorless oil.

LC-MS (Method 7): R _t = 0.82min

MS (ES +): m / z = 267.1 (M + H) ⁺

Example 150A [(2S) -3-oxobut-2-yl] carbamic acid benzyl ester

Under argon, 1000 mg of benzyl {(2S) -1- [methoxy (methyl) amino] -1-oxoprop-2-yl} carbamate (Example 148A, 3.8 mmol, 1 (Equivalent) was dissolved in 19.5 ml of THF and cooled to -78 ° C. At this temperature, 4 ml of a 1.4M solution of 1.4M methyl magnesium bromide in 1: 3 THF / toluene (6 mmol, 1.5 equivalents) was slowly added. The mixture was stirred at -78 ° C for 5 min and at RT for 1 h and then left at RT overnight. Then add 0.27 ml of water under ice cooling, and The mixture was concentrated. The residue was diluted with water and a 1N aqueous hydrochloric acid solution and extracted four times with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. This gave 813 mg (88% of theory; 90% purity) of the title compound.

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 222.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.17 (d, 3 H), 2.08 (s, 3 H), 4.04 (m, 1 H), 5.04 (s, 2 H), 7.29-7.39 ( m, 5 H), 7.67 (d, 1 H).

Example 151A [(2R) -3-oxobut-2-yl] benzyl carbamate

Under argon, 1000 mg of benzyl {(2R) -1- [methoxy (methyl) amino] -1-oxoprop-2-yl} carbamate (Example 149A, 3.8 mmol, 1 (Equivalent) was dissolved in 19.5 ml of THF and cooled to -78 ° C. At this temperature, 4 ml of a 1.4M solution of 1.4M methyl magnesium bromide in 1: 3 THF / toluene (6 mmol, 1.5 equivalents) was slowly added. The mixture was stirred at -78 ° C for 5 min and at RT for 1 h and then left at RT overnight. Then, 0.27 ml of water was added under ice-cooling, and then the mixture was concentrated. The residue was diluted with water and a 1N aqueous hydrochloric acid solution and extracted four times with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. This gave 888 mg (97% of theory) of the title compound as a colorless oil.

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 222.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.17 (d, 3 H), 2.08 (s, 3 H), 3.99-4.10 (m, 1 H), 5.03 (s, 2 H), 7.27- 7.41 (m, 5 H), 7.68 (d, 1 H).

Example 152A 3-bromo-N- (4-fluorophenyl) propanamide

5.75 ml of 4-fluoroaniline (6.65 g, 59.88 mmol, 1 equivalent) was first placed in 65 ml of THF, and 33 ml of a 2M trimethylaluminum hexane solution (65.87 mmol, 1.1 equivalent) was added at -78 ° C and The mixture was stirred for 20 min and slowly raised to RT. At -20 ° C, this solution was added dropwise to a solution of 6.54 ml (10 g, 59.8 mmol, 1 eq.) Of methyl 3-bromopropionate in 65 ml of THF and then stirred at RT for 3 h. The reaction solution was carefully acidified with 1N aqueous hydrochloric acid solution and extracted twice with ethyl acetate at 0 ° C. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 12.6 g (67% of theory; 78% purity) of the title compound, which was further reacted without purification.

LC-MS (Method 7): R _t = 0.83min

MS (ES +): m / z = 248.0 (M + H) ⁺

Example 153A 3-bromo-N- [4- (trifluoromethyl) phenyl] propanamide

Similarly to Example 152A, 22.3 ml of 4- (trifluoromethyl) aniline (29 g, 179.6 mmol, 1 equivalent) was reacted with 19.6 ml (30 g, 179.6 mmol, 1 equivalent) of 3-bromopropanoic acid methyl ester and subjected to subsequent treatment . The crude product obtained was then purified on a silica gel column (mobile phase: dichloromethane). This gave 20.3 g (37% of theory) of the title compound.

LC-MS (Method 7): R _t = 1.03min

MS (ES +): m / z = 296.0 (M + H) ⁺

Example 154A 1- (4-fluorophenyl) azepine-2-one

12.60 g of 3-bromo-N- (4-fluorophenyl) propanamide (Example 152A, 39.94 mmol, 1 equivalent) was first placed in 97.1 ml of dichloromethane, and 11.19 g of 1,4,7 was added , 10,13,16-hexaoxane octadecane (18-crown-6, 42.33 mmol, 1.06 equivalent) and 2.33 g of potassium hydroxide (41.54 mmol, 1.04 equivalent) and the mixture was stirred at RT overnight. Then 0.35 equivalents of 1,4,7,10,13,16-hexaoxane octadecane and 0.35 equivalents of potassium hydroxide were added and the mixture was stirred at RT overnight. A saturated aqueous ammonium chloride solution was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried and filtered with sodium sulfate, and the filtrate was concentrated and purified [column: Reprosil C18, 10 μm, Spring Column 470 x 50mm; acetonitrile / water gradient; flow rate: 200ml / min; 22 ° C; wavelength: 210nM ]. This gave 3.46 g (38% of theory) of the title compound.

LC-MS (Method 7): R _t = 0.77min

MS (ES +): m / z = 166.1 (M + H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.08 (t, 2 H), 3.62 (t, 2 H), 7.18-7.28 (m, 2 H), 7.33-7.40 (m, 2 H).

Example 155A 1- [4- (trifluoromethyl) phenyl] azepine-2-one

20.30 g of 3-bromo-N- [4- (trifluoromethyl) phenyl] propanamide (Example 153A, 66.16 mmol, 1 equivalent) was first placed in 161 ml of dichloromethane, and 18.54 g of 1 , 4,7,10,13,16-hexaoxane octadecane (18-crown-6, 70.13 mmol, 1.06 equivalents) and 3.86 g of potassium hydroxide (68.81 mmol, 1.04 equivalents) and the mixture was at RT Stir until overnight. Add saturation Aqueous ammonium chloride solution and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated. This gave 25.0 g (86% of theory; purity about 49%) of the title compound, which was further reacted without purification.

LC-MS (Method 7): R _t = 0.94min

MS (ES +): m / z = 216.1 (M + H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.14 (t, 2 H), 3.70 (t, 2 H), 7.51 (d, 2 H), 7.73 (d, 2 H).

Example 156A 6-fluoro-2,3-dihydroquinolin-4 (1H) -one

500 mg of 1- (4-fluorophenyl) azepine-2-one (Example 154A, 3.03 mmol, 1 equivalent) was first placed in 24 ml of dichloromethane, and 0.5 ml of trifluoromethanesulfonic acid was added at 0 ° C. (909 mg, 6.05 mmol, 2 eq.) And the mixture was stirred at RT for 45 min. An additional 0.3 equivalents of trifluoromethanesulfonic acid was added twice, and the mixture was stirred for 30 min after each addition. Under ice cooling, a saturated aqueous sodium bicarbonate solution was carefully added and the reaction mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 284 mg (57% of theory) of the title compound.

LC-MS (Method 7): R _t = 0.69min

MS (ES +): m / z = 166.1 (M + H) ⁺

Example 157A 6- (trifluoromethyl) -2,3-dihydroquinolin-4 (1H) -one

Similarly to Example 156A, 18.77 g of 1- [4- (trifluoromethyl) phenyl] azepine-2-one (Example 155A, 42.74 mmol, 1 equivalent) was reacted and subsequently processed. The resulting crude product was purified on a silica gel column (mobile phase: cyclohexane / ethyl acetate gradient: from 7: 3 to 5: 1). This gave 1.75 g (16% of theory; 86% purity) of the title compound.

LC-MS (Method 2): R _t = 0.89min

MS (ES +): m / z = 216.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.59 (t, 2 H), 3.46-3.55 (m, 2 H), 6.90 (d, 1 H), 7.53 (dd, 2 H), 7.80 ( s, 1 H).

Example 158A 6-fluoro-4-oxo-3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester

294 mg of 6-fluoro-2,3-dihydroquinolin-4 (1H) -one (Example 156A, 1.78 mmol, 1 equivalent) was first placed in 12.8 ml of THF, and 466 mg of di-tert-butyl dicarbonate was added Ester (2.14 mmol, 1.2 equivalents) and 44 mg of 4-dimethylaminopyridine (0.36 mmol, 0.2 equivalents) and the mixture was stirred at RT for 1 h and 15 min. Then another 0.2 equivalents of di-t-butyl dicarbonate was added and the mixture was stirred at RT overnight. The reaction solution was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified on a silica gel column (mobile phase: cyclohexane / Ethyl acetate 7: 3). This gave 394 mg (81% of theory) of the title compound.

LC-MS (Method 5): R _t = 2.30min

MS (ES +): m / z = 266.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.50 (s, 9 H), 2.77 (t, 2 H), 4.08 (t, 2 H), 7.44-7.54 (m, 2 H), 7.79 ( dd, 1 H).

Example 159A 4-oxo-6- (trifluoromethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester

Similarly to Example 158A, 1.75 g of 6- (trifluoromethyl) -2,3-dihydroquinolin-4 (1H) -one (Example 157A, 7.0 mmol, 1 equivalent) were subjected to reaction and subsequent treatment. The crude product was purified on a silica gel column (mobile phase: cyclohexane / ethyl acetate 4: 1). This gave 1.72 g (74% of theory) of the title compound.

LC-MS (Method 7): R _t = 1.27min

MS (ES +): m / z = 360.0 (M-H + HCOOH) ^-

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.52 (s, 9 H), 2.83 (t, 2 H), 4.15 (t, 2 H), 7.89-7.95 (m, 1 H), 8.01- 8.09 (m, 2 H).

Example 160A Racemic-4-amino-6-fluoro-3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl trifluoroacetate

295 mg of 6-fluoro-4-oxo-3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (Example 158A, 1.11 mmol, 1 equivalent) was first placed in 3.5 ml of ethanol In this step, 1285 mg of amine acetate (16.68 mmol, 15 equivalents) and 84 mg of sodium cyanoborohydride (1.33 mmol, 1.2 equivalents) were added and the mixture was reacted in a microwave oven at 130 ° C for 2 min. The reaction solution was concentrated and the residue was treated in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% TFA). This gave 185 mg (43% of theory) of the title compound.

LC-MS (Method 7): R _t = 0.56min

MS (ES +): m / z = 267.2 (M + H) ⁺

Example 161A Racemic-4-amino-6- (trifluoromethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester

1.3 g of 4-oxo-6- (trifluoromethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (Example 159A, 4 mmol, 1 equivalent) were placed in advance 12.6 ml of ethanol was added, and 4.6 g of amine acetate (59.5 mmol, 15 equivalents) and 0.3 g of sodium cyanoborohydride (4.8 mmol, 1.2 equivalents) were added. The reaction mixture was separated and the portions were irradiated in a microwave oven at 130 ° C for 1 min. The mixture was then concentrated and the residue was treated in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified on silica gel (mobile phase: dichloromethane / ethyl acetate: 5/1, then dichloromethane / methanol: 10/1). This gave 0.84 g (78% of theory) of the title compound.

LC-MS (Method 7): R _t = 0.69min

MS (ES +): m / z = 317.1 (M + H) ⁺

Example 162A (2,6-difluorophenyl) ( ² H ₂ ) methanol

2.0 g of methyl 2,6-difluorobenzoate (11.6 mmol, 1 eq.) Was first placed in 40 ml of THF at 0 ° C, and 23.2 ml of a 1 M solution of lithium aluminum deuteride in THF was slowly added at this temperature. (23.2 mmol, 2 equivalents). The mixture was stirred for 45 min, and then 1.2 ml of water, 1.2 ml of a 2N aqueous sodium hydroxide solution, and 2.3 ml of water were successively added. The resulting precipitate was filtered and thoroughly washed with THF. The filtrate was concentrated and the residue was reacted further without purification. This gave 1.77 g (104% of theory) of the title compound.

GC-MS (Method 6): R _t = 2.38min

MS (EIpos): m / z = 146.1 (M) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 5.20 (s, 1 H), 7.02-7.12 (m, 2 H), 7.24-7.44 (m, 1 H).

Example 163A Racemic-1-amino-3-azabicyclo [4.1.0] heptane-3-carboxylic acid benzyl ester trifluoroacetate

530 mg of racemic-3-azabicyclo [4.1.0] heptan-1-amine dihydrochloride (2.86 mmol, 1 equivalent; according to Gensini, M .; Kozhushkov, SI; Yufit, DS; Howard, JAK; Es-Sayed, M .; De Meijere, A .; prepared by Eur. J. Org. Chem., 2002, p. 2499-2507) Dissolved in 11.8 ml of 1,4-bis Alkane and 14.3 ml of a 1N aqueous sodium hydroxide solution. At 0 ° C, 0.3 ml of benzyl chloroformate (366 mg, 2.15 mmol, 0.75 equivalents) in 8.8 ml of 1,4-dichloromethane was added dropwise over 30 min. An alkane solution. The solution was then slowly warmed to RT and stirred at RT for 30 min. The mixture was removed under reduced pressure The alkane was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% TFA / formic acid). This gave 428 mg (41% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 247.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.58 (t, 1 H), 1.01-1.13 (m, 1 H), 1.38-1.47 (m, 1 H), 1.49-1.63 (m, 1 H ), 1.93-2.07 (m, 1 H), 2.89-3.10 (m, 1 H), 3.91-4.11 (m, 1 H), 5.08 (s, 2 H), 7.24-7.43 (m, 5 H), 8.28 (br.s, 3 H), [the other signal is hidden under the solvent peak].

Example 164A [2- (3,3-Difluoropyrrolidin-1-yl) ethyl] third butyl carbamic acid

Put 900 mg of 3,3-difluoropyrrolidine hydrochloride (6.27 mmol, 1 equivalent) first Into 62 ml of acetonitrile, add 1475 mg of tert-butyl (2-bromoethyl) carbamate (6.58 mmol, 1.05 equivalents) and then 3.28 ml of N, N-diisopropylethylamine (2.43 g, 18.81 mmol, 3 eq.) and the mixture was stirred at 80 ° C. overnight. Then, 0.5 equivalent of 3,3-difluoropyrrolidine hydrochloride (450 mg, 3.14 mmol) was added and the reaction solution was continuously stirred at 80 ° C. overnight. The reaction solution was concentrated and purified on a silica gel column (mobile phase: cyclohexane / ethyl acetate gradient: from 5/1 to pure ethyl acetate). This gave 431 mg (28% of theory) of the title compound.

GC-MS (Method 6): R _t = 4.81min

MS (ES +): m / z = 251.0 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (s, 9 H), 2.13-2.27 (m, 2 H), 2.44 (t, 2 H), 2.68 (t, 2 H), 2.87 ( t, 2 H), 2.97-3.05 (m, 2 H), 6.76 (t, 1 H).

Example 165A {2-[(2-methoxyethyl) amino] ethyl} third butyl carbamate

1.57 g of (2-bromoethyl) carbamic acid third butyl ester (7.0 mmol, 0.7 equivalent) was first put into 98.5 ml of acetonitrile, and 0.87 ml of 2-methoxyethylamine (750 mg, 10.0 mmol) was added. , 1 equivalent) and 3.5 ml of N, N-diisopropylethylamine (2.58 g, 20 mmol, 2 equivalents) and the mixture was stirred at 80 ° C. overnight. The mixture was concentrated and the residue was purified on a silica gel column (mobile phase: dichloromethane / methanol gradient: from 50: 1 to 30: 1 to 10: 1, then dichloromethane / 2N ammonia methanol solution: 10: 1 ). This gave 1.69 g (99% of theory; purity of about 90%) of the title compound.

MS (Method 10, ES +): m / z = 219.1 (M + H) ⁺

Example 166A [2- (4,4-difluoropiperidin-1-yl) ethyl] tert-butyl carbamate

0.90 g of 4,4-difluoropiperidine hydrochloride (5.71 mmol, 1 equivalent) was first put into 56 ml of acetonitrile, and 1.41 g of (2-bromoethyl) carbamic acid third butyl ester (6.28 mmol) was added. , 1.1 equivalents) and 3 ml of N, N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equivalents) and the mixture was stirred at 80 ° C. overnight. Add two equivalents of 0.4 equivalent of tert-butyl (2-bromoethyl) carbamate to the reaction solution and continue stirring at 80 ° C. until overnight. The mixture was concentrated and purified on a silica gel column (gradient: from cyclohexane / ethyl acetate: 3: 1 to ethyl acetate). This gave 1.28 g (62% of theory; 73% purity) of the title compound.

GC-MS (Method 6): R _t = 4.87min

MS (EIpos): m / z = 191.1 (M-73) ⁺

MS (Method 10, ES +): m / z = 265.2 (M + H) ⁺

Example 167A 2- (3,3-difluoropyrrolidin-1-yl) ethylamine hydrochloride

8.6 ml of a 2N solution of hydrogen chloride in ether (17.22 mmol, 10 equivalents) was added to 431 mg of [2- (3,3-difluoropyrrolidin-1-yl) ethyl] carbamic acid third butyl ester (Example 164A, 1.72 mmol, 1 equivalent), and the reaction mixture was stirred at RT overnight. The solvent was then decanted, the residue was triturated with ether three times, and the residue obtained in this way was dried under reduced pressure. This gave 410 mg (99% of theory; 93% purity) of the title compound.

MS (Method 10, ES +): m / z = 151.1 (M-2HCl + H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.07-3.23 (m, 2 H), 3.28-4.13 (m, 8 H), 8.34 (br.s, 4 H).

Example 168A N- (2-methoxyethyl) ethyl-1,2-diamine dihydrochloride

15.5 ml of a 2N solution of hydrogen chloride in diethyl ether (31 mmol, 10 equivalents) was added to 750 mg of {2-[(2-methoxyethyl) amino] ethyl} carbamic acid third butyl ester (Example 165A, purity about 90%, 3.1 mmol, 1 equivalent), and the mixture was stirred at RT overnight. The solvent was decanted, the residue was triturated three times with ether and the product obtained in this way was dried under reduced pressure. This gave 482 mg (82% of theory) of the title compound.

MS (Method 10, ES +): m / z = 119 (M-2HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.11-3.24 (m, 6 H), 3.30 (s, 3 H), 3.61 (t, 2 H), 8.19 (br.s, 3 H), 9.16 (br.s, 2 H).

Example 169A 2- (4,4-difluoropiperidin-1-yl) ethylamine dihydrochloride

6.9 ml of a 2N solution of hydrogen chloride in ether (13.8 mmol, 10 equivalents) was added to 500 mg of [2- (4,4-difluoropiperidin-1-yl) ethyl] carbamic acid third butyl ester (Example 166A, 1.38 mmol, 1 equivalent), and the mixture was stirred at RT overnight. The solvent was decanted, the residue was triturated with ether three times, the ether was decanted and the product obtained in this way was dried under reduced pressure. This gave 448 mg (100% of theory; 73% purity) of the title compound.

MS (Method 10, ES +): m / z = 165.1 (M-2HCl + H) ⁺

Example 170A Enantiomer- [2- (3,4-difluorophenyl) -2-{[((8-{[(2,6-difluorophenyl) ( ² H ₂ ) methyl] oxy} -2- Methyl imidazo [1,2-a] pyridin-3-yl) carbonyl] amino} ethyl] carbamic acid third butyl ester

1222 mg of enantiomer- [2- (3,4-difluorophenyl) -2-{[((8-hydroxy-2-methylimidazo [1,2-a] pyridin-3-yl) carbonyl] Amino} ethyl] third butyl carbamate (Example 131A, 2.7 mmol, 1 equivalent) was suspended in 16.5 ml of toluene, and 600 mg of (2,6-difluorophenyl) ( ² H ₂ ) Methanol (Example 162A, 4.1 mmol, 1.5 equiv.) And 1148 mg of triphenylphosphine (4.4 mmol, 1.6 equiv.). Under ice-cooling, 12 ml of THF and 0.9 ml of diisopropyl azodicarboxylate (942 mg, 4.4 mmol, 1.6 equivalents) were added and the mixture was stirred at RT for 2 days and left at RT for 2 days. The solution was extracted three times with ethyl acetate and the combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product obtained was pre-separated on a silica gel column (Biotage Isolera SNAP-Cartrige KP-Sil 100g; mobile phase: cyclohexane / ethyl acetate: from 12% to 100%) and then repurified by preparative HPLC ( Method 9). This gave 255 mg (16% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.11min

MS (ES +): m / z = 575.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.32 (s, 9 H), 2.58 (s, 3 H), 3.37-3.46 (m, 1 H), 5.12-5.19 (m, 1 H), 6.91 (t, 1 H), 7.02 (d, 1 H), 7.09 (t, 1 H), 7.19-7.27 (m, 3 H), 7.36-7.51 (m, 2 H), 7.54-7.65 (m, 1 H), 8.22 (d, 1 H), 8.55 (d, 1 H), [the other signal is hidden under the solvent peak].

The examples shown in Table 10A are similar to Example 34A by 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid and an appropriate commercially available amine are described in General Procedure 2 Prepared by reaction under reaction conditions.

An exemplary subsequent treatment of the reaction mixture: adding water to the reaction solution and stirring the formed precipitate for another 0.5-1.0 h, filtering, washing with water and drying under high vacuum overnight. Alternatively, the precipitate or reaction mixture is further purified directly by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA) and dried under high vacuum overnight. If necessary, the product fractions were treated in ethyl acetate or dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate or dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

Example 179A {4-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino) ] -2-methylbut-2-yl} carbamate tert-butyl trifluoroacetate

75 mg of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 16A, 0.21 mmol, (1 equivalent), 82 mg of (benzotriazol-1-yloxy) bisdimethylamino-methylium fluoroborate (TBTU, 0.26 mmol, 1.2 equivalents), and 108 mg of 4-methylmorpholine (1.06 mmol, 5 eq.) Was first placed in 1.45 ml of DMF. After 10 min at RT, 56 mg (0.23 mmol, 1.1 equivalents) of (4-amino-2-methylbut-2-yl) carbamic acid tert-butyl ester hydrochloride was added and the mixture was stirred at RT overnight. Water and trifluoroacetic acid were added and the reaction solution was purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). This gave 118 mg (84% of theory) of the title compound.

LC-MS (Method 1): R _t = 1.43min

MS (ES +): m / z = 537.0 (M-TFA + H) ⁺

The examples shown in Table 11A are similar to Example 179A by 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3- A carboxylic acid (Example 16A) was prepared by reacting an appropriate commercially available or homemade amine under the reaction conditions described in General Procedure 2:

Example 181A: {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] Ethyl} carbamate tert-butyl trifluoroacetate

60 mg of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 21A, 0.18 mmol, 1 (Equivalent), 70 mg of (benzotriazol-1-yloxy) bisdimethylamino-methylium fluoroborate (TBTU, 0.22 mmol, 1.2 equivalents), and 73 mg of 4-methylmorpholine ( 0.72 mmol, 4 equivalents) was first placed in 1.3 ml of DMF. After 10 min at RT, 32 mg of (2-aminoethyl) tributylcarbamate (0.2 mmol, 1.1 equivalents) were added and the mixture was stirred at RT overnight. Water and trifluoroacetic acid were added and the reaction solution was purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). This gave 93 mg (87% of theory) of the title compound.

LC-MS (Method 7): R _t = 0.88min

MS (ES +): m / z = 475.2 (M + H) ⁺

The examples shown in Table 12A are similar to Example 181A by An acid (Example 21A) was prepared by reacting an appropriate commercially available or homemade amine under the reaction conditions described in General Procedure 2:

¹⁾ Coupling agent: HATU

The examples shown in Table 13A are similar to Example 34A prepared by reacting a suitable carboxylic acid with a suitable commercially available amine under the reaction conditions described in General Procedure 2.

An exemplary subsequent treatment of the reaction mixture: adding water to the reaction solution and stirring the formed precipitate for another 0.5-1.0 h, filtering, washing with water and drying under high vacuum overnight. another One option is to further purify the precipitate or reaction mixture directly by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA) and dry under high vacuum overnight. If necessary, the product fractions were treated in ethyl acetate or dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate or dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

¹⁾ Use of excess amine because the exact purity is unknown.

Example 191A {(2S) -3-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] but-2-yl} carbamic acid benzyl ester

164 mg of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 16A, 0.47 mmol, 1 equivalent) dissolved in 1.4 ml of DMF, 145 mg of [(2S) -3-aminobut-2-yl] carbamic acid benzyl ester (Example 141A, 0.65 mmol, 1.4 equivalents), 230 mg of O- (7 -azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU, 0.6 mmol, 1.3 equivalents) and 180.7 mg of N, N-diisopropylethylamine (0.23 ml, 1.4 mmol, 3 equivalents) and the mixture was stirred at RT overnight. A drop of water was then added and the precipitated solid was filtered and dried under reduced pressure. This gave 160 mg (53% of theory; 86% purity) of the title compound as colorless crystals.

LC-MS (Method 1): R _t = 2.50min

MS (ES +): m / z = 557.1 (M + H) ⁺

Example 192A (2S) -2-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) -Amino] methyl} pyrrolidine-1-carboxylic acid tert-butyl trifluoroacetate

75 mg of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 (Equivalent), 90 mg of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU, 0.24 mmol, 1.05 eq) and 88 mg of N, N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 eq) were first placed in 1.4 ml of DMF and stirred at RT for 20 min. 50 mg (0.25 mmol, 1.1 equivalents) of (2S) -2- (aminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester was then added and the mixture was stirred at RT overnight. The reaction solution was then diluted with water / TFA and purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 143 mg (99% of theory; 98% purity) of the title compound.

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 515.3 (M-TFA + H) ⁺

Example 193A (2R) -2-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) -Amino] methyl} pyrrolidine-1-carboxylic acid tert-butyl trifluoroacetate

75 mg of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 (Equivalent), 90 mg of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU, 0.24 mmol, 1.05 eq) and 88 mg of N, N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 eq) were first placed in 1.4 ml of DMF and stirred at RT for 20 min. Then 50 mg (0.25 mmol, 1.1 equivalents) of (2R) -2- (aminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester was added and the mixture was stirred at RT overnight. The reaction solution was diluted with water / TFA and purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). This gave 108 mg (76% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 515.3 (M-TFA + H) ⁺

Example 194A 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (2-oxoethyl) imidazo [1,2-a] pyridine-3-carboxamide

Under argon, 1.65 g of 1,1,1-triethylfluorenyloxy-1λ ⁵ , 2-benzoiodo The azole-3 (1H) -one (Dess-Martin periodinane, 3.9 mmol, 1.5 equivalents) was first placed in 20 ml of dichloromethane. Slowly add 1 g of 8-[(2,6-difluorobenzyl) oxy] -N- (2-hydroxyethyl) -2-methylimidazo- [1,2- a] A solution of pyridine-3-carboxamide (Example 175A, 2.6 mmol, 1 equivalent) in 32 ml of dichloromethane. The reaction mixture was stirred overnight and warmed to RT. The reaction solution was then diluted with about 160 ml of ethyl acetate and washed three times with a 1 N aqueous sodium hydroxide solution. The organic phase was washed with a saturated aqueous sodium chloride solution until neutral, dried over sodium sulfate, filtered and concentrated. This gave 879 mg (47% of theory; about 50% purity) of the title compound, which was further reacted without purification.

LC-MS (Method 2): R _t = 0.56min

MS (ES-): m / z = 358 (MH) ^-

Example 195A 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N-[(2R) -1-oxoprop-2-yl] imidazo [1,2-a] pyridine- 3-carboxamide

Similar to Example 194A, 500 mg of 8-[(2,6-difluorobenzyl) oxy] -N-[(2R) -1-hydroxyprop-2-yl] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (Example 177A, 1.33 mmol) was oxidized with 847 mg (2.0 mmol) of Dess-Martin periodinane plus 0.11 ml of pyridine (105 mg, 1.33 mmol) and subsequently processed. This gave 440 mg (53% of theory; 60% purity) of the title compound, which was further reacted without purification.

LC-MS (Method 2): R _t = 0.64min

MS (ES-): m / z = 372.1 (MH) ⁺

Example 196A 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N-[(2S) -1-oxoprop-2-yl] imidazo [1,2-a] pyridine- 3-carboxamide

Similar to Example 194A, 500 mg of 8-[(2,6-difluorobenzyl) oxy] -N-[(2S) -1-hydroxyprop-2-yl] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (Example 178A, 1.33 mmol, 1 equivalent) was oxidized with Dess-Martin periodinane plus 0.11 ml of pyridine (105 mg, 1.33 mmol, 1 equivalent) and subsequently processed. This gave 439 mg (53% of theory; 60% purity) of the title compound, which was further reacted without purification.

LC-MS (Method 5): R _t = 1.49min

MS (ES-): m / z = 372.1 (MH) ⁺

Example 197A Enantiomer- {2- (3,4-difluorophenyl) -2-[({8-[(2-fluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine -3- Group} carbonyl) amino] ethyl} carbamic acid third butyl ester

200 mg of enantiomer- [2- (3,4-difluorophenyl) -2-{[((8-hydroxy-2-methylimidazo [1,2-a] pyridin-3-yl) carbonyl] Amino} ethyl] third butyl carbamate (Example 131A, 0.45 mmol, 1 equivalent), 93 mg of 2-fluorobenzyl bromide (0.49 mmol, 1.1 equivalent), and 321 mg of cesium carbonate (0.99 mmol, 2.2 equivalent) Stir in 10 ml of DMF at RT overnight. 150 ml of water were then added and the mixture was stirred at RT for 15 min. The precipitated product was filtered off and dried under reduced pressure. This gave 190 mg (79% of theory; 91% purity) of the title compound.

LC-MS (Method 1): R _t = 1.06min

MS (ES +): m / z = 555.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.33 (s, 9 H), 2.58 (s, 3 H), 3.37-3.47 (m, 2 H), 5.10-5.22 (m, 1 H), 5.32 (s, 2 H), 6.89 (t, 1 H), 6.97 (d, 1 H), 7.08 (t, 1 H), 7.20-7.34 (m, 3 H), 7.37-7.52 (m, 3 H ), 7.61 (t, 1 H), 8.22 (d, 1 H), 8.53 (d, 1 H).

The examples shown in Table 14A are similar to Example 197A by enantiomer- [2- (3,4-difluorophenyl) -2-{[(8-hydroxy-2-methylimidazo [1,2-a ] Pyridin-3-yl) carbonyl] amino} ethyl] carbamic acid tert-butyl ester (Example 131A) was prepared by reacting a suitable commercially available benzyl bromide:

Example 202A: Enantiomer-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- 6-fluoro-3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (mirromeric isomer A)

198 mg of Example 172A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol, flow rate: 15 ml / min; 40 ° C, detection: 220nm].

Yield: mirror isomer A: 76 mg (99% ee)

Mirror isomer A: R _t = 4.20min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 25% isohexane, 75% ethanol, flow rate: 1ml / min; 40 ° C, detection: 220nm ].

Example 203A: Enantiomer-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- 6-fluoro-3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (mirromeric isomer B)

198 mg of Example 172A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol, flow rate: 15 ml / min; 40 ° C, detection: 220nm].

Yield Mirror Isomer B: 76 mg (99% ee)

Mirror isomer B: R _t = 9.13min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 25% isohexane, 75% ethanol, flow rate: 1ml / min; 40 ° C, detection: 220nm ].

Example 204A: Enantiomer-4-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3,4-dihydroquinoline-1 (2H) carboxylic acid third butyl ester (mirror isomer A)

190 mg of Example 180A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 30% isohexane, 70% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm].

Yield: mirror isomer A: 64 mg (99% ee)

Mirror isomer A: R _t = 4.84min [Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 30% isohexane, 70% ethanol + 0.2% diethylamine, flow rate: 1ml / min; 40 ℃, detection: 220nm].

Example 205A: Enantiomer-4-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3,4-dihydroquinoline-1 (2H) carbamic acid third butyl ester (mirror isomer B)

190 mg of Example 180A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 30% isohexane, 70% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm].

Yield: mirror isomer B: 65 mg (99% ee)

Mirror isomer B: R _t = 5.62min [Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 30% isohexane, 70% ethanol + 0.2% diethylamine, flow rate: 1ml / min; 40 ℃, detection: 220nm].

Example 206A: Enantiomer-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amine Propyl] -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (mirromeric isomer A)

188 mg of Example 173A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm].

Yield Mirror Isomer A: 80mg (99% ee)

Mirror isomer A: R _t = 7.44min [Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 220nm].

Example 207A: Enantiomer-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- 3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (mirror isomer B)

188 mg of Example 173A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm].

Yield Mirror Isomer B: 81mg (99% ee)

Mirror isomer B: 10.05min [Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, Detection: 220nm].

Example 208A: Enantiomer-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- 6- (trifluoromethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (mirror isomer A)

149 mg of Example 174A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 20 ml / min; 25 ° C, detection: 230nm].

Yield of image isomer A: 56mg (100% ee)

Mirror isomer A: R _t = 3.90min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 25 ° C; detection : 220nm].

Example 209A: Enantiomer-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- 6- (trifluoromethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (mirror isomer B)

149 mg of Example 174A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 20 ml / min; 25 ° C, detection: 230nm].

Yield: mirror isomer B: 55mg (100% ee)

Mirror isomer B: R _t = 7.60min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 25 ° C; detection : 220nm].

Example 210A: Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-methoxypropyl} carbamic acid benzyl ester (mirror isomer A)

290 mg of Example 186A was dissolved in 3.5 ml of ethanol and separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol , Flow rate: 20ml / min; 25 ° C, detection: 220nm].

Yield Mirror Isomer A: 58mg (100% ee)

Mirror isomer A: R _t = 5.47min [Daicel Chiralpak OD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.55 (s, 3H; hidden by DMSO signal), 3.20-3.35 (m, 2H), 3.25 (s, 3H), 3.39-3.49 (m, 2H) , 4.20-4.31 (m, 1H), 5.00 (s, 2H), 5.31 (s, 2H), 6.90 (t, 1H), 7.00 (d, 1 H), 7.20-7.30 (m, 7H), 7.40 ( t, 1H), 7.52 (d, 1H), 7.54-7.64 (m, 1H), 8.60 (d, 1H).

Example 211A: Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-methoxypropyl} carbamic acid benzyl ester (mirror isomer B)

290 mg of Example 186A was dissolved in 3.5 ml of ethanol and separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol , Flow rate: 20ml / min; 25 ° C, detection: 220nm].

Yield: mirror isomer B: 53 mg (95% ee)

Mirror isomer B: R _t = 6.998min [Daicel Chiralpak OD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 212A: Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] Benzyl-3- (3,4-difluorophenoxy) propyl} carbamate (Mirror Isomer B)

350 mg of Example 187A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AH-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol, flow rate: 15 ml / min; 45 ° C, detection: 220nm].

Yield: mirror isomer B: 110 mg (99% ee)

Mirror isomer B: R _t = 7.66min [Daicel Chiralcel OD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 213A: Enantiomer- {3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpropyl} carbamic acid third butyl ester (mirromeric isomer A)

192 mg of Example 185A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 15% ethanol, 15% isopropanol, Flow rate: 25ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer A: 68 mg (100% ee)

Mirror isomer A: R _t = 8.65min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 70% isohexane, 15% ethanol, 15% isopropanol, flow rate: 1.5ml / min; 30 ° C, detection: 220nm].

Example 214A: Enantiomer- {3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpropyl} carbamic acid third butyl ester (mirror isomer B)

195 mg of Example 185A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 15% ethanol, 15% isopropanol, Flow rate: 25ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer B: 79 mg (87% ee)

Mirror isomer B: 9.24min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 70% isohexane, 15% ethanol, 15% isopropanol, flow rate: 1.5ml / min; 30 ° C, Detection: 220nm].

Example 215A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -4,4,4-trifluorobut-2-yl} carbamate (mirror isomer A)

280 mg of Example 189A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 18 ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer A: 80mg (100% ee)

Mirror isomer A: R _t = 8.79min [Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 1.0ml / min; 30 ° C, detection: 220nm].

Example 216A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -4,4,4-trifluorobut-2-yl} carbamate (mirror isomer B)

280 mg of Example 189A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 18 ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer B: 94mg (99% ee)

Mirror isomer B: R _t = 11.63min [Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 1.0ml / min; 30 ° C, detection: 220nm].

Example 217A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -4,4,4-trifluorobut-2-yl} benzyl carbamate (Mirror Isomer A)

260 mg of Example 190A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 15 ml / min; 40 ° C, detection: 220nm].

Yield: mirror isomer A: 85mg (> 99% ee)

Mirror isomer A: R _t = 4.81min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% TFA + 1% water, flow rate: 1.0 ml / min; 45 ° C, detection: 220nm].

Example 218A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -4,4,4-trifluorobut-2-yl} benzyl carbamate (mirror isomer B)

260 mg of Example 190A was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 15 ml / min; 40 ° C, detection: 220nm].

Yield: mirror isomer B: 92 mg (99% ee)

Mirror isomer B: R _t = 6.59min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% TFA + 1% water, flow rate: 1.0 ml / min; 45 ° C, detection: 220nm].

Example 219A 1- (azepine-3-yl) pyrrolidine dihydrochloride

1.00 g (4.42 mmol) of 3- (pyrrolidin-1-yl) azepine-1-carboxylic acid tert-butyl ester was first placed in 5.3 ml of 1,4-bis To the alkane, add 5.3 ml of 4N hydrochloric acid The alkane solution was stirred at RT overnight. The reaction mixture was then concentrated, foamed with dichloromethane and dried under high vacuum. This gave 950 mg (99% of theory; 92% purity) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.82-1.94 (m, 2 H), 1.94-2.05 (m, 2 H), 2.89-3.00 (m, 2 H), 4.07-4.19 (m, 2 H), 4.28-4.42 (m, 3 H), 9.11 (br.s, 1 H), 9.49 (br.s, 1 H), 12.33 (br.s, 1 H).

Example 220A {2- [3- (Pyrrolidin-1-yl) azepine-1-yl] ethyl} carbamic acid third butyl ester

595 mg of 1- (azepine-3-yl) pyrrolidine dihydrochloride (Example 219A, 2.75 mmol, about 92% purity, 1 equivalent) was reacted in 3 batches. The free base was obtained and 1- (azepine-3-yl) pyrrolidinium dihydrochloride was passed through a StratoSpheres ™ SPE column. At this point, the column was first wetted with 1 ml of methanol. 1- (azepine-3-yl) pyrrolidine dihydrochloride was dissolved in 3 ml of methanol, then passed through a column and the column was flushed with methanol. The resulting solution was concentrated (the column retained approximately 0.9 mmol of salt). The free base was then placed in 26.8 ml of acetonitrile, and 656 mg of 2- (Boc-amino) ethyl bromide (2.9 mmol, 1.05 equivalents) and 1.45 ml of N, N-diisopropylethylamine ( 8.25 mmol, 3 eq.) And the mixture was stirred at 80 ° C overnight. The reaction mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 5: 1; dichloromethane / methanol 10: 1; dichloromethane / methanol 4: 1 and dichloromethane / 1N ammonia methanol). Solution 4: 1). This gave 463 mg (67% of theory) of the title compound.

DCI-MS (Method 4): m / z = 270.2 (M + H) ⁺

Example 221A 2- [3- (pyrrolidin-1-yl) azepine-1-yl] ethylamine dihydrochloride

460 mg of {2- [3- (pyrrolidin-1-yl) azepine-1-yl] ethyl} third butyl formate (example 220A, 1.7 mmol, 1 equivalent) was first placed in 8.54 ml of 2N Ether solution of hydrochloric acid and 1 ml of diethyl ether And the mixture was stirred at RT overnight. The precipitated solid was filtered, washed with diethyl ether and dried under reduced pressure. This gave 390 mg (94% of theory) of the title compound.

DCI-MS (Method 4): m / z = 170.2 (M + H) ⁺

Example 222A 1- (aminomethyl) cyclobutylamine

750 mg of 1-aminocyclobutanenitrile (7.8 mmol, 1 equivalent) was first placed in 16.5 ml of THF, and 23.4 ml of a 1 N lithium aluminum hydride solution in THF (23.4 mmol, 3 eq.) and the mixture was stirred at RT for 3.5 h. Subsequently, 0.8 ml of water, 0.8 ml of a 2N aqueous sodium hydroxide solution, and 1.6 ml of water were continuously added to the reaction mixture. The formed solid was filtered off and washed with methanol. The filtrate was concentrated. This gave 1980 mg (76% of theory; estimated purity 30%) of the title compound, which was further reacted without purification.

FIA-MS (Method 10, ES +): m / z = 101 (M + H) ⁺

Example 223A Racemic-4,4,4-trifluorobutane-1,2-diamine dihydrochloride

130 mg of racemic- (1-amino-4,4,4-trifluorobut-2-yl) carbamic acid benzyl ester trifluoroacetate (Example 147A, 0.33 mmol, 1 equivalent) was first placed in 8.4 In ml of methanol, 35 mg (0.03 mmol) of palladium on 10% activated carbon was added under argon and the mixture was hydrogenated at RT and atmospheric pressure overnight. The mixture was then filtered through Millipore ^® filters, ether solution of 2N hydrochloric acid was added 0.33ml (0.66mmol, 2 eq) was added and the mixture was concentrated. This gave 72 mg (100% of theory) of the title compound.

FIA-MS (Method 10, ES +): m / z = 143.0 (M-2HCl + H) ⁺

Example 224A Racemic-3-isopropoxypropane-1,2-diamine dihydrochloride

Under argon, 218 mg (0.71 mmol, 87% purity) of the racemic- (2-amino-3-isopropoxypropyl) carbamic acid benzyl ester from Example 76A was first placed in ethanol (5.0 ml ), And 76 mg (0.07 mmol) of 10% activated carbon on palladium and 2.2 ml (21.36 mmol) of cyclohexane were added. The reaction mixture was stirred at reflux overnight. The mixture was then filtered through a Millipore® filter, the filter cake was washed with ethanol, 0.7 ml (1.42 mmol) of a 2M solution of hydrogen chloride in ether was added to the filtrate, and the mixture was concentrated and dried under high vacuum. This gave 190 mg (99% of theory, 76% purity) of the target compound.

DCI-MS (Method 4): m / z = 133 (M-2HCl + H) ⁺

Example 225A 3- (dibenzylamino) oxo-3-carbonitrile

0.63 ml (10.8 mmol) of oxan-3-one and 3.6 ml (27.1 mmol) of trimethylcyanosilane were added to a solution of 10.4 ml (54.1 mmol) of dibenzylamine in 72 ml of acetic acid. The reaction mixture was then stirred at RT overnight. The mixture was then concentrated, the residue was dissolved in water / diethyl ether and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed twice with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate from 40: 1 to 30: 1). This gave 2.39 g (77% of theory, 97% purity) of the target compound.

LC-MS (Method 13): R _t = 2.53min.

MS (ESI +): m / z = 279 (M + H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.49 (s, 4H), 4.29 (d, 2H), 4.37 (d, 2H), 7.26-7.39 (m, 10H).

Example 226A 3- (aminomethyl) oxo-3-amine dihydrochloride

585 mg (2.07 mmol) of 3- (aminomethyl) -N, N-dibenzyloxyfluoren-3-amine [synthetic system is described in: US2008 / 103183 A1, 2008; p. 48] is first put into ethanol (29.2 ml), and 441 mg (0.41 mmol) of palladium on 10% activated carbon and 6.3 ml (62.2 mmol) of cyclohexene were added. The reaction mixture was stirred at reflux for 8 h. The mixture was then filtered through a Millipore® filter, the filter cake was washed with methanol, 2.6 ml (5.2 mmol) of a 2M hydrogen chloride in ether solution was added to the filtrate, and the mixture was concentrated and dried under high vacuum to obtain 423 mg (87% (Theoretical value, purity 75%) of the target compound.

DCI-MS (Method 4): m / z = 103 (M-2HCl + H) ⁺

Example 227A Racemic- {1-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl (Amino) amino] -3-methylbut-2-yl} carbamic acid tert-butyl ester

200 mg (0.57 mmol) of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 16A, 191 mg (0.60 mmol) of HATU and 0.19 ml (1.70 mmol) of 4-methylmorpholine in DMF (3.6 ml) were stirred at RT for 20 min. 126 mg (0.62 mmol) of racemic- (1-amino-3-methylbut-2-yl) carbamic acid third butyl ester was then added and the reaction mixture was stirred at RT overnight. Water / TFA was then added and the mixture was purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 264 mg (87% of theory, 100% purity) of the target compound.

LC-MS (Method 2): R _t = 1.23min.

MS (ESI +): m / z = 537 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (d, 3H), 0.91 (d, 3H), 1.32 (s, 9H), 1.66-1.78 (m, 1H), 2.47 (s, 3H, The signal part is hidden by the DMSO peak), 3.20-3.29 (m, 1H), 3.38-3.46 (m, 1H), 3.49-3.60 (m, 1H), 5.34 (s, 2H), 6.62 (d, 1H), 7.19 (d, 1H), 7.22-7.29 (m, 2H), 7.56-7.66 (m, 1H), 7.81 (t, 1H), 8.74 (d, 1H).

Example 228A Enantiomer- {1-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] -3-methylbut-2-yl} carbamic acid tert-butyl ester (mirror isomer A)

260 mg of Example 227A was separated into mirror isomers on the opposite palm phase by preparative separation [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, flow rate : 20ml / min; 40 ° C, detection: 220nm].

Mirror isomer A: Yield: 124 mg (99% ee)

R _t = 3.84min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 40 ° C; detection: 220nm].

Example 229A Enantiomer- {1-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] -3-methylbut-2-yl} carbamic acid tert-butyl ester (mirror isomer B)

260 mg of Example 227A was separated into mirror isomers on the opposite palm phase by preparative separation [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, flow rate : 20ml / min; 40 ° C, detection: 220nm].

Mirror isomer B: Yield: 122 mg (99% ee)

R _t = 5.97min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 40 ° C; detection: 220nm].

Example 230A Racemic- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] -3-methylbut-2-yl} carbamic acid third butyl ester

200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 203 mg (0.63 mmol) of HATU and 0.20 ml (1.81 mmol) of 4-methylmorpholine were first placed in DMF (3.8 ml), the mixture was stirred at RT for 20 min, and 134 mg (0.66 mmol) of racemic (1-Amino-3-methylbut-2-yl) carbamic acid tert-butyl ester and the reaction mixture was stirred at RT overnight. Water / TFA was added and the mixture was purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 262 mg (84% of theory, 100% purity) of the target compound.

LC-MS (Method 2): R _t = 1.03min.

MS (ESI +): m / z = 517 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (d, 3H), 0.90 (d, 3H), 1.33 (s, 9H), 1.68-1.78 (m, 1H), 2.31 (s, 3H) , 2.46 (s, 3H), 3.18-3.28 (m, 1H), 3.38-3.46 (m, 1H), 3.50-3.59 (m, 1H), 5.28 (s, 2H), 6.63 (d, 1H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.64 (m, 1H), 7.67 (t, 1H), 8.47 (s, 1H).

Example 231A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3-methylbut-2-yl} carbamic acid tert-butyl ester (mirror isomer A)

260 mg of Example 230A was separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralpak IA, 5 μm, 250 x 20 mm, mobile phase: 50% acetonitrile, 50% third butyl methyl ether, Flow rate: 20ml / min; 25 ° C, detection: 220nm].

Mirror isomer A: Yield: 89 mg (100% ee)

R _t = 4.04min [Daicel Chiralpak IA, 5 μm, 250 x 4.6mm; mobile phase: 50% acetonitrile, 50% third butyl-methyl ether; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 232A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3-methylbut-2-yl} carbamic acid tert-butyl ester (mirror isomer B)

260 mg of Example 230A was separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralpak IA, 5 μm, 250 x 20 mm, mobile phase: 50% acetonitrile, 50% third butyl methyl ether, Flow rate: 20ml / min; 25 ° C, detection: 220nm].

Mirror isomer B: Yield: 93 mg (100% ee)

R _t = 6.02min [Daicel Chiralpak IA, 5 μm, 250 x 4.6mm; mobile phase: 50% acetonitrile, 50% third butyl methyl ether; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 233A Racemic- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino ] -3-methylbut-2-yl} carbamic acid tert-butyl ester

The title compound was prepared and purified similarly to Example 230A. 200 mg (0.63 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid and 140 mg (0.69 mmol) of racemic 1-amino-3-methylbut-2-yl) carbamic acid tert-butyl ester as a starting material, and 215 mg (68% of the theoretical value, purity 100%) of the target compound were obtained.

LC-MS (Method 2): R _t = 1.02min.

MS (ESI +): m / z = 503 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (d, 3H), 0.90 (d, 3H), 1.33 (s, 9H), 1.68-1.78 (m, 1H), 2.54 (s, 3H, Concealed by DMSO signal), 3.19-3.28 (m, 1H), 3.39-3.46 (m, 1H), 3.50-3.59 (m, 1H), 5.30 (s, 2H), 6.64 (d, 1H), 6.93 (t , 1H), 7.01 (d, 1H), 7.20-7.28 (m, 2H), 7.54-7.63 (m, 1H), 7.70 (t, 1H), 8.63 (d, 1H).

Example 234A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-methylbut-2-yl} carbamic acid tert-butyl ester (mirror isomer A)

210mg of Example 233A was separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralpak IA, 5 μm, 250 x 20mm, mobile phase: 20% acetonitrile, 80% third butyl methyl ether, Flow rate: 20ml / min; 25 ° C, detection: 230nm].

Mirror isomer A: Yield: 89 mg (100% ee)

R _t = 4.69min [Daicel Chiralpak IA, 5 μm, 250 x 4.6mm; mobile phase: 20% acetonitrile, 80% third butyl methyl ether; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 235A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-methylbut-2-yl} carbamate tert-butyl ester (mirror isomer B)

210mg of Example 233A was separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralpak IA, 5 μm, 250 x 20mm, mobile phase: 20% acetonitrile, 80% third butyl methyl ether, Flow rate: 20ml / min; 25 ° C, detection: 230nm].

Mirror isomer B: Yield: 73 mg (100% ee)

R _t = 7.29min [Daicel Chiralpak IA, 5 μm, 250 x 4.6mm; mobile phase: 20% acetonitrile, 80% third butyl methyl ether; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 236A 3- (benzyloxy) -5-bromopyridine-2-amine

200 g (1 mol) of 2-amino-3-benzyloxypyridine was first placed in 4 l of dichloromethane, and 62 ml (1.2 mol) of bromine in 620 ml of dichloromethane was added at 0 ° C during 30 minutes Methane solution. After the addition was completed, the reaction solution was stirred at 0 ° C for 60 min. Then about 41 saturated aqueous sodium bicarbonate solution was added to the mixture. The organic phase was separated and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 6: 4) and the product was concentrated in fractions. This gave 214 g (77% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.92min

MS (ES +): m / z = 279 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.16 (s, 2H), 5.94-6.00 (m, 2H), 7.26-7.29 (m, 1H), 7.31-7.36 (m, 1H), 7.37- 7.43 (m, 2H), 7.47-7.52 (m, 2H), 7.57-7.59 (m, 1H).

Example 237A 8- (Benzyloxy) -6-bromo-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 200 g (0.72 mol) of 3- (benzyloxy) -5-bromopyridine-2-amine, 590 g (3.58 mol) of ethyl 2-chloroacetamidoacetate, and 436 g of 3A molecular sieve were suspended Ethanol at 61 and stirred at reflux for 72 h. The reaction mixture was filtered through silica gel and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 9: 1, then 6: 4) and the product was concentrated in fractions. This gave 221 g (79% of theory) of the target compound.

LC-MS (Method 7): R _t = 1.31min

MS (ES +): m / z = 389 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.36 (t, 3 H), 2.58 (s, 3 H), 4.32-4.41 (m, 2 H), 5.33 (s, 2 H), 7.28- 7.32 (m, 1 H), 7.36-7.47 (m, 3 H), 7.49-7.54 (m, 2 H), 8.98 (d, 1 H).

Example 238A 8- (Benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 105 g (270 mmol) of 8- (benzyloxy) -6-bromo-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 237A was suspended in 4.2 1,4-two of l To the alkane, 135.4 g (539 mmol, 50% purity) of trimethylboroxane, 31.2 g (27 mmol) of tris (triphenylphosphine) palladium (0), and 78.3 g (566 mmol) of potassium carbonate were continuously added. The mixture was stirred at reflux for 8 h. The reaction mixture was cooled to RT, the precipitate was filtered off with silica gel and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (dichloromethane: ethyl acetate = 9: 1). This gave 74 g (84.6% of theory; 100% purity) of the target compound.

LC-MS (Method 7): R _t = 1.06min

MS (ES +): m / z = 325 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.35 (t, 3 H), 2.34 (br.s, 3 H), 2.56 (s, 3 H), 4.31-4.38 (m, 2 H), 5.28 (br.s, 2 H), 6.99-7.01 (m, 1 H), 7.35-7.47 (m, 3 H), 7.49-7.54 (m, 2 H), 8.68-8.70 (m, 1 H).

Example 239A 8-Hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

74 g (228 mmol) of 8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 238A was first placed in 1254 ml of dichloromethane and In 251 ml of ethanol, 20.1 g of 10% activated carbon on palladium (wet with 50% water) was added under argon. The reaction mixture was hydrogenated at RT and atmospheric pressure until overnight. The reaction mixture was filtered through silica gel and concentrated. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 95: 5). This gave 50.4 g (94% of theory) of the target compound.

DCI-MS: (Method 4) (ES +): m / z = 235.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.35 (t, 3 H), 2.27 (s, 3 H), 2.58 (s, 3 H), 4.30-4.38 (m, 2 H), 6.65 ( d, 1 H), 8.59 (s, 1 H), 10.57 (br.s, 1 H).

Example 240A Racemic-2-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] methyl} -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester

120 mg (0.36 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Example 21A of imidazo [1,2-a] pyridine-3-carboxylic acid, 139 mg (0.43 mmol) of TBTU and 0.20 ml (1.81 mmol) of 4-methylmorpholine in DMF (2.3 ml) at RT Stir for 10 min, add 119 mg (0.40 mmol) of racemic-2- (aminomethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester hydrochloride and add the reaction mixture Stir at RT until overnight. Water was added and the mixture was stirred at RT for 30 min. The formed solid was filtered off, washed with water and dried under high vacuum. This gave 182 mg (85% of theory, 98% purity) of the target compound.

LC-MS (Method 7): R _t = 1.13min.

MS (ESI +): m / z = 577 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.38 (s, 9H), 1.64-1.75 (m, 1H), 2.10-2.20 (m, 1H), 2.22 (s, 3H), 2.30 (s, 3H), 2.56-2.62 (m, 1H), 2.66-2.76 (m, 1H), 3.09-3.19 (m, 1H), 3.55-3.64 (m, 1H), 4.63-4.72 (m, 1H), 5.27 ( s, 2H), 6.90 (s, 1H), 6.99 (t, 1H), 7.05-7.15 (m, 2H), 7.19-7.28 (m, 2H), 7.37 (d, 1H), 7.54-7.64 (m, 1H), 7.80 (t, 1H), 8.40 (s, 1H).

Example 241A 2-methyl-4-phenyl-2- (trifluoromethyl) -1,3- Azodin (diastereomers)

45 g (328.0 mmol) of racemic-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluenesulfonate were added to 55.13 g (492.0 mmol) of 1,1,1 -A solution of trifluoroacetone in toluene (1.35 l). The reaction mixture was boiled on a water separator under reflux for 16 h. The mixture was cooled to 0 ° C and the formed solid was filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, 85% purity) of the target compound.

LC-MS (Method 2): R _t = 0.99min

MS (ESI +): m / z = 232 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.54 (s, 3H), 3.56 (t, 1H), 3.81 (d, 1H), 4.28 (t, 1H), 4.35-4.43 (m, 1H) , 7.29-7.47 (m, 5H).

Example 242A 3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl) amino] -2-methylpropionitrile (diastereomer)

Under argon, 52.8 g (228.3 mmol) of 2-methyl-4-phenyl-2- (trifluoromethyl) -1,3- Azodin (diastereomer) Example 241A was first placed in dichloromethane (2l) and cooled to 0 ° C. Slowly add 42.85 ml (342.5 mmol) of trimethylcyanosilane and 42.1 ml (342.5 mmol) of the boron trifluoride / ether complex and stir the mixture at RT for 16 h. The reaction solution was then poured into 1.5 l of a saturated sodium bicarbonate solution. Then another 400 g of sodium bicarbonate was added, and the solution was adjusted to pH 10 with a concentrated sodium hydroxide aqueous solution. The aqueous solution was extracted three times with 500 ml of dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 56.8 g (96% of theory, 2 diastereomers) of the target compound.

LC-MS (Method 2): R _t = 0.89min and 0.93min.

MS (ESIneg): m / z = 303 (M-H + HCOOH) ^- .

Example 243A 2-[(3-Amino-1,1,1-trifluoro-2-methylprop-2-yl) amino] -2-phenylethanol (diastereomer)

31 g (120.0 mmol) of 3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl) amine Example] 242A methyl acetonitrile 242A was first put into a third butyl methyl ether (3.1 l), the mixture was cooled to 0 ° C, 18.25 g (480.2 mmol) of lithium aluminum hydride was added and the reaction mixture was stirred at RT 16h. The mixture was then cooled to 0 ° C and quenched with 24 ml of water, and then 24 ml of a 15% strength potassium hydroxide aqueous solution and 48 ml of water were added. The resulting mixture was filtered through silica gel and washed with tert-butyl methyl ether. The organic phase was separated, dried over sodium sulfate, filtered and concentrated. This gave 29.2 g (83% of theory, purity 89%) of the target compound.

LC-MS (Method 2): R _t = 0.52min

MS (ESI +): m / z = 263 (M + H) ⁺ .

Example 244A {3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl) amino] -2-methylpropyl} carbamic acid third butyl ester (diastereomer)

29.1 ml (209.8 mmol) of triethylamine and 23.98 g (109.9 mmol) of di-t-butyl dicarbonate (dissolved in 286 ml of THF) were added to 26.2 g (99.9 mmol) of 2-[(3-amine -1,1,1-trifluoro-2-methylprop-2-yl) amino] -2-phenylethanol (diastereomer) Example 243A in a THF solution (500 ml). The reaction mixture was stirred at RT for 16 h. The mixture was then concentrated and treated with 500 ml of a saturated aqueous sodium bicarbonate solution and ethyl acetate each time, the phases were separated and the organic phase was dried over sodium sulfate, filtered and concentrated. This gave 39.80 g (110% of theory) of the title compound, which was used in the next step without further purification.

FIA-MS (Method 10, ES +): m / z = 363 (M + H) ⁺

Example 245A Racemic- (2-amino-3,3,3-trifluoro-2-methylpropyl) carbamic acid third butyl ester

Under argon, 39 g (107.6 mmol) of {3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl) amino] -2-methyl-propyl} amine The third butyl formate example 244A was first put into ethanol (700 ml), and 5.44 g (53.8 mmol) of palladium (II) hydroxide (20% on activated carbon, wet with about 60%) was added. The reaction mixture was hydrogenated at atmospheric pressure for 16 h. The mixture was then filtered through silica gel and concentrated. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate gradient: from 9/1 to 6/4). This gave 15.8 g (61% of theory) of the target compound.

FIA-MS (Method 10, ES +): m / z = 243 (M + H) ⁺

¹ H NMR (400MHz, CDCl ₃ ): δ = 1.22 (s, 3H), 1.45 (s, 9H), 3.13-3.23 (m, 1H), 3.37-3.48 (m, 1H), 4.89 (br.s, 1H).

Example 246A Racemic-3,3,3-trifluoro-2-methylpropan-1,2-diamine dihydrochloride

188ml of 4M hydrogen chloride bis Add hexane solution to 15 g (61.9 mmol) of racemic- (2-amino-3,3,3-trifluoro-2-methylpropyl) carbamic acid third butyl ester bis from Example 245A. Hexane (188ml) solution. The reaction mixture was stirred at RT for 16 h and then concentrated and kept under argon. This gave 14.4 g (108% of theory) of the target compound, which was not further purified.

FIA-MS (Method 10, ES +): m / z = 143 (M-2HCl + H) ⁺

¹ H NMR (400 MHz, D ₂ O): δ = 1.40 (s, 3H), 3.21-3.31 (m, 2H).

Example 247A Enantio- (2-amino-3-methoxypropyl) benzyl carbamate (mirror isomer A)

After removing the TFA of the sample with a silicone-based adsorbent "Bond Elut PSA" (manufacturer: Agilent), 10 g of Example 140A was separated into mirror isomers by preparative separation on the counter phase [Column: Daicel Chiralpak AY-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm].

Mirror isomer A: Yield: 2.17 g (96% ee)

R _t = 5.79min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection : 220nm].

Example 248A Enantio- (2-amino-3-methoxypropyl) benzyl carbamate (mirror isomer B)

After removing the TFA of the sample with a silicone-based adsorbent "Bond Elut PSA" (manufacturer: Agilent), 10 g of Example 140A was separated into mirror isomers by preparative separation on the counter phase [Column: Daicel Chiralpak AY-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm].

Mirror isomer B: Yield: 2.07 g (94% ee)

R _t = 7.26min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection : 220nm].

Example 249A Enantiomer-3-methoxypropan-1,2-diamine dihydrochloride (mirror isomer A)

Under argon, 750 mg (3.15 mmol) of enantio- (2-amino-3-methoxypropyl) carbamic acid benzyl ester (Mirror Isomer A) Example 247A was first placed in ethanol (22 ml) In addition, 335 mg (0.32 mmol) of palladium on 10% activated carbon and 9.6 ml (94.42 mmol) of cyclohexene were added. The reaction mixture was stirred at reflux for 7 h. Then 335 mg (0.32 mmol) of 10% activated carbon on palladium was added and the mixture was stirred under reflux for another two days. The reaction mixture was cooled to RT, filtered through a Milipore filter and the filter cake was washed with ethanol. 3.2 ml (6.3 mmol) of a 2N solution of hydrogen chloride in ether was added to the filtrate and the mixture was concentrated and dried under high vacuum. This gave 440 mg (79% of theory) of the target compound.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.03-3.11 (m, 2H), 3.32 (s, 3H), 3.55-3.64 (m, 3H), 8.31-8.69 (m, 4H).

Example 250A Enantiomer-3-methoxypropan-1,2-diamine dihydrochloride (mirromeric isomer B)

The title compound was prepared and purified similarly to Example 249A. Starting with 750 mg (3.15 mmol) of benzyl enanti- (2-amino-3-methoxypropyl) carbamate (mirror isomer B) from Example 248A, 454 mg (81% of Theoretical value).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 3.03-3.11 (m, 2H), 3.32 (s, 3H), 3.55-3.64 (m, 3H), 8.31-8.69 (m, 4H).

Example 251A 2,6-Dimethyl-8- (3-methylbutoxy) imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Add 1.23 ml (9.4 mmol) of 1-iodo-3-methylbutane and 6.12 g (18.8 mmol) of cesium carbonate to 2.0 g (8.5 mmol) of 8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester Example 239A in 122.3 ml of a DMF solution, and the mixture was stirred at 60 ° C. for 40 min. 900 ml of water was added to the reaction mixture, which was cooled to RT and the mixture was stirred at RT for 1 h, and the precipitated solid was filtered, washed with water and dried under high vacuum. This gave 2.25 g (84% of theory; 97% purity) of the title compound.

LC-MS (Method 7): R _t = 1.12min

MS (ES +): m / z = 305 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.96 (d, 6H), 1.35 (t, 3H), 1.70 (q, 2H), 1.77-1.89 (m, 1H), 2.33 (s, 3H) , 2.56 (s, 3H), 4.17 (t, 2H), 4.34 (q, 2H), 6.88 (s, 1H), 8.64 (s, 1H).

Example 252A 2,6-dimethyl-8- (3-methylbutoxy) imidazo [1,2-a] pyridine-3-carboxylic acid

2.25 g (7.4 mmol) of 2,6-dimethyl-8- (3-methylbutoxy) imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester Example 251A was first placed in 157 ml In THF / methanol 5: 1, 37 ml (37 mmol) of a 1 N lithium hydroxide solution was added and the reaction mixture was stirred at RT over the weekend. The mixture was then cooled to 0 ° C, acidified to pH 4 with 6N hydrochloric acid and the organic solvents were removed under reduced pressure. The precipitated solid was filtered, washed with water and dried under high vacuum. This gave 1.64 g (80% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.71min

MS (ES +): m / z = 277 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.96 (d, 6H), 1.70 (q, 2H), 1.78-1.89 (m, 1H), 2.32 (s, 3H), 2.56 (s, 3H) , 4.17 (t, 2H), 6.85 (s, 1H), 8.69 (s, 1H), 12.86-13.08 (m, 1H).

Example 253A Racemic-2-{[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino ] Methyl} -3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester

Add 145 mg (0.45 mmol) of TBTU and 0.2 ml (1.89 mmol) of 4-methylmorpholine to 120 mg (0.38 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2- Methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A in 2.4 ml of DMF solution, and the mixture was stirred at RT for 10 min. 124 mg (0.42 mmol) of racemic-2- (aminomethyl) -3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester hydrochloride was added and the reaction mixture was stirred at RT Until overnight. Water was added and the reaction mixture was stirred at RT for 30 min. The precipitated solid was filtered, washed with water and dried under high vacuum. This gave 190 mg (90% of theory; 100% purity) of the title compound.

LC-MS (Method 7): R _t = 1.13min

MS (ES +): m / z = 563 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.38 (s, 9H), 1.64-1.75 (m, 1H), 2.11-2.21 (m, 1H), 2.25 (s, 3H), 2.65-2.76 ( m, 2H), 3.10-3.20 (m, 1H), 3.57-3.66 (m, 1H), 4.68 (five-fold, 1H), 5.29 (s, 2H), 6.91 (t, 1H), 6.96-7.03 ( m, 2H), 7.08 (t, 1H), 7.13 (d, 1H), 7.19-7.27 (m, 2H), 7.37 (d, 1H), 7.54-7.63 (m, 1H), 7.83 (t, 1H) , 8.58 (d, 1H).

Example 254A Enantiomer-{(1R, 2R) -2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] cyclohexyl} carbamic acid third butyl ester

The title compound was prepared and purified similarly to Example 253A. 80 mg (0.24 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A and 57 mg (0.27 mmol) of enantiomer- (1R, 2R) -trans-N-Boc-1,2-cyclohexanediamine as a starting material, yielding 107 mg (83% of theoretical value; purity 98%) of the target Compound.

LC-MS (Method 7): R _t = 1.02min

MS (ES +): m / z = 529 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.16-1.45 (m, 13H), 1.61-1.74 (m, 2H), 1.76-1.86 (m, 1H), 1.89-1.99 (m, 1H), 2.30 (s, 3H), 2.46 (s, 3H), 3.37-3.46 (m, 1H), 3.67-3.78 (m, 1H), 5.28 (s, 2H), 6.81 (d, 1H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 2H), 8.46 (s, 1H).

Example 255A Racemic-8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

5.50 g (23.5 mmol) of 8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester Example 239A, 4.46 g (28.2 mmol) of 1- (2 , 6-Difluorophenyl) ethanol, 5.35 ml (27.0 mmol) of diisopropyl azodicarboxylate and 7.08 g (27.0 mmol) of triphenylphosphine were dissolved in 141 ml of THF and stirred at RT for 2 h. 0.70 ml (3.5 mmol) of diisopropyl azodicarboxylate and 0.62 g (2.3 mmol) of triphenylphosphine were added to the reaction mixture, and the reaction solution was stirred at RT for 1 h. The precipitated solid was filtered and dried under high vacuum. This gave 4.6 g (52.8% of theory; 100% purity) of the title compound. The filtrate was concentrated and purified twice by silica gel chromatography (cyclohexane: ethyl acetate gradient = from 8: 1 to 4: 1). All product-containing fractions were repurified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave an additional 2.16 g (25% of theory) of the target compound.

LC-MS (Method 2): R _t = 1.08min

MS (ES +): m / z = 375 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.34 (t, 3H), 1.79 (d, 3H), 2.25 (s, 3H), 2.58 (s, 3H), 4.33 (q, 2H), 6.17 (q, 1H), 6.73 (s, 1H), 7.06-7.16 (m, 2H), 7.37-7.48 (m, 1H), 8.67 (s, 1H).

Example 256A Enantiomer-8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester (mirror isomeric Structure B)

6.8 g of Example 255A was separated into mirrors on the opposite palm phase by preparative separation Image isomers [column: Daicel Chiralpak AD-H, 5 μm, 250 x 30 mm, mobile phase: 70% isohexane, 30% ethanol, flow rate: 50 ml / min; 40 ° C, detection: 210 nm].

Mirror isomer B: Yield: 2.7 g (98.4% ee)

R _t = 5.18min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 257A Enantiomer-8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (mirror isomer B)

2.58 g (6.9 mmol) of enantio-8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 -Example of ethyl carboxylate (mirromeric isomer B) 256A was dissolved in 154 ml of THF / methanol 5: 1, 34.5 ml (34.5 mmol) of a 1 N aqueous lithium hydroxide solution was added and the mixture was stirred at 40 ° C for 5 h. The reaction mixture was cooled to RT, acidified with 6N hydrochloric acid solution and concentrated. The solid was filtered off, washed with water and dried under high vacuum. This gave 2.26 g (95% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 347 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.79 (d, 3H), 2.24 (s, 3H), 2.57 (s, 3H), 6.16 (q, 1H), 6.67 (s, 1H), 7.06 -7.16 (m, 2H), 7.38-7.48 (m, 1H), 8.74 (s, 1H), 12.24-13.90 (br.s, 1H).

Example 258A 2,6-dimethyl-8- [4,4,4-trifluoro-3- (trifluoromethyl) butoxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Add 7.89 g (24.2 mmol) of cesium carbonate and 2.30 g (8.88 mmol) of 4,4, -trifluoro-3- (trifluoromethyl) butyl bromide to 1.89 g (8.07 mmol) of 8-hydroxy- In 60 ml of DMF solution of 2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester Example 239A, the reaction mixture was stirred at RT for 90 min. Then 60 ml of water was added, the precipitated solid was filtered and the filtrate residue was washed twice with 100 ml of water and 20 ml of tert-butyl methyl ether. The precipitate precipitated from the filtrate was filtered and washed with the filtrate. The two filtrate residues were treated in 50 ml of ethyl acetate. The solution was concentrated under reduced pressure and the residue was dried under reduced pressure overnight. This gave 2.25 g of the target compound (95% purity, 64% of theory).

LC-MS (Method 2): R _t = 1.16min

MS (ES +): m / z = 413 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.36 (t, 3H), 2.34 (s, 3H), 2.32-2.38 (m, 2H), 2.58 (s, 3H), 4.18-4.30 (m, 1H), 4.31-4.38 (m, 4H), 6.93 (s, 1H), 8.71 (s, 1H).

Example 259A 2,6-dimethyl-8- [4,4,4-trifluoro-3- (trifluoromethyl) butoxy] imidazo [1,2-a] pyridine-3-carboxylic acid

Add 3.28 g (10.4 mmol) of barium hydroxide octahydrate to 1.95 g (4.73 mmol) of 2,6-dimethyl-8- [4,4,4-trifluoro-3- (trifluoromethyl) ) Butoxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester Example 258A in 30 ml of a methanol solution, and the mixture was stirred at RT for 3 days. The suspension was diluted with 30 ml of water and adjusted to pH 6 with 1 M hydrochloric acid. The solid was filtered off, washed with 50 ml of water and dried under reduced pressure at 70 ° C for 2 h. This gave 1.64 g of the target compound (90% purity, 81% of theory).

LC-MS (Method 2): R _t = 0.78min

MS (ES +): m / z = 385 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.29 (s, 3H), 2.28-2.37 (m, 2H), 2.56 (s, 3H), 4.22-4.35 (m, 3H), 6.74 (s, 1H), 8.99 (s, 1H).

Example 260A Racemic-2-amino-4- (benzyloxy) -2-methylbutyronitrile

6.37 g (119.1 mmol) of ammonium chloride (dissolved in 15 ml of warm water) and 9 ml (216.6 mmol) of concentrated ammonia were added to an aqueous solution of 5.31 g (108.3 mmol) of sodium cyanide in 10 ml. Then 19.3 g (108.3 mmol) of 4- (benzyloxy) butan-2-one dissolved in 3 ml of ethanol was added. The mixture was stirred at RT for 15 min and at 60 ° C for 2 h. Another 4 g (81.6 mmol) of sodium cyanide, 4.8 g (89.7 mmol) of ammonium chloride, and 6.5 ml (156.4 mmol) of concentrated ammonia were added and mixed. The mixture was stirred for an additional 2 h at 60 ° C. The reaction solution was then cooled and 300 ml each of dichloromethane and water were added. After phase separation, the aqueous phase was extracted with 300 ml of dichloromethane. The combined organic phases were dried and concentrated. The crude product was purified on silica gel (cyclohexane / ethyl acetate gradient 6 / 4-1 / 1). This gave 19.9 g of the target compound (77% purity, 69% of theory).

LC-MS (Method 11): R _t = 2.31min

MS (ES +): m / z = 205 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (s, 3H), 1.81-1.94 (m, 2H), 2.57 (br.s, 2H), 3.58-3.69 (m, 2H), 4.48 ( s, 2H), 7.25-7.38 (m, 5H).

Example 261A Racemic-4- (benzyloxy) -2-methylbutyl-1,2-diamine

Add 0.59 ml (1.59 mmol) of lithium aluminum hydride (1N solution in diethyl ether) to 0.5 g (2.45 mmol) of 2-amino-4- (benzyloxy) -2-methyl under argon at 0 ° C. Butyronitrile Example 260A in 25 ml of anhydrous THF. The reaction solution was stirred at 0 ° C for 30 min and then for another 1 h while slowly warming to room temperature. Carefully add 245 μl of water, 245 μl of a 2N aqueous sodium hydroxide solution, and 490 μl of water. The precipitate was filtered and washed with THF and methanol, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 20/1, isocratic). This gave 0.30 g of the target compound (96% purity, 57% of theory).

LC-MS (Method 11): R _t = 1.94min

MS (ES +): m / z = 209 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.90 (s, 3H), 1.56 (t, 2H), 2.27-2.38 (m, 2H), 3.45-3.60 (m, 2H), 4.42 (s, 2H), 7.22-7.36 (m, 5H).

Example 262A Racemic-2-amino-3- (benzyloxy) -2-methylpropionitrile

Put 5.07g (27.79mmol) of 1- (benzyloxy) acetone into 55.6ml of 2N ammonia methanol solution, add 1.53g (31.12mmol) of sodium cyanide and 3.71g (31.12mmol) of ammonium chloride and The mixture was heated at reflux for 2 h. Then another 27.4 ml of a 2N ammonia methanol solution was added, and the reaction mixture was stirred under reflux for 2 h. The reaction solution was cooled and diluted with 90 ml of dichloromethane. The obtained solid was filtered off and the filtrate was concentrated. The residue was purified using silica gel (mobile phase: cyclohexane / ethyl acetate gradient: from 4/1 to 1/1). This gave 4.94 g of the target compound (90% purity, 84% of theory).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 191 (M + H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 1.34 (s, 3H), 3.29-3.44 (m, 2H), 4.59 (s, 2H), 7.26-7.39 (m, 5H).

Example 263A Racemic-3- (benzyloxy) -2-methylpropan-1,2-diamine

Under argon and -78 ° C, 20.9 ml (20.9 mmol) of lithium aluminum hydride (1N in diethyl ether) was added to 6.8 g (32.17 mmol, about 90% purity) of 2-amino-3- (benzyloxy) ) -2-Methylpropionitrile Example 262A in 329 ml of anhydrous THF. The reaction solution was -1 ° C at -78 ° C, 2h at -20 ° C and 2h at 0 ° C. Then carefully add 3.22 ml of water, 3.22 ml of a 2N aqueous sodium hydroxide solution, and 6.44 ml of water. The precipitate was filtered and washed with THF and methanol, and the filtrate was concentrated. Thus 8 g of a crude product was obtained, and 7 g of this crude product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = from 20/1 to 10/1). This gave 1.52 g of the target compound (about 28% of theory).

LC-MS (Method 11): R _t = 2.05min

MS (ES +): m / z = 195 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88 (s, 3H), 1.39 (br.s, 2H), 2.30-2.47 (m, 2H), 3.12-3.22 (m, 2H), 4.44 ( s, 2H), 7.24-7.38 (m, 5H).

Example 264A 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

3.00 g (12.81 mmol) of 8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester Example 239A, 3.27 g (14.1 mmol) of 2- (bromo) Methyl) -1,3,4-trifluorobenzene and 9.18 g (28.17 mmol) of cesium carbonate were first put into 183 ml of anhydrous DMF and heated in an oil bath for 30 min. The temperature was raised to 60 ° C. Then about 1.8 I of water was added and the mixture was stirred for 30 min. The solid was filtered off, washed with water and dried under reduced pressure. This gave 5.07 g of the title compound (99% of theory; purity of about 96%).

LC-MS (Method 2): R _t = 1.14min

MS (ES +): m / z = 379 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.35 (t, 3 H); 2.36 (s, 3 H); 2.55 (s, 3 H; overlap with DMSO signal); 4.36 (q, 2 H) ; 5.35 (s, 2 H); 7.09 (s, 1 H); 7.22-7.32 (m, 1 H); 7.60-7.73 (m, 1 H); 8.72 (s, 1 H).

Example 265A 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid

5.07 g (12.87 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid ethyl Ester Example 264A was dissolved in 275 ml of THF / methanol (5/1), 64.4 ml of a 1 N aqueous lithium hydroxide solution was added, and the mixture was stirred at 40 ° C. for 3.5 h. The mixture was acidified to a pH of about 4 with a 6N aqueous hydrochloric acid solution at 0 ° C and concentrated. The formed solid was filtered off, washed with water and dried under reduced pressure. This gave 4.77 g (98% of theory; purity of about 93%) of the title compound.

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 351 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.37 (s, 3 H); 2.54 (s, 3 H; overlap with DMSO signal); 5.36 (s, 2 H); 7.11 (s, 1 H) ; 7.25-7.33 (m, 1 H); 7.61-7.73 (m, 1 H); 8.78 (s, 1 H); 13.10 (br.s, 1 H).

Example 266A 4-fluoro-2-nitropyridin-3-ol

Under ice cooling, 500 mg (3.43 mmol) of 4-fluoropyridin-3-ol hydrochloride was carefully dissolved in 3.2 ml of concentrated sulfuric acid, and 0.21 ml of concentrated nitric acid was carefully added at 0 ° C. The reaction was warmed to RT and stirred at RT overnight. The mixture was then added to 10 g of ice and 6 ml of a 45% strength sodium hydroxide aqueous solution was added dropwise under ice cooling. The resulting precipitate was filtered and then Dry under reduced pressure overnight. This gave 191 mg (36% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.36min

MS (ES-): m / z = 157 (MH) ^-

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 7.69 (dd, 1 H); 7.95-8.01 (m, 1 H); 11.97 (br.s, 1 H).

Example 267A 2-amino-4-fluoropyridin-3-ol

Under argon, 90 mg (0.57 mmol) of 4-fluoro-2-nitropyridin-3-ol Example 266A was dissolved in 30 ml of ethanol, a spoon of 10% activated carbon on palladium was added and the mixture was hydrogenated at RT atmospheric pressure 1.5h. The mixture was then filtered through silica gel and the filter cake was washed with plenty of ethanol. The solution was concentrated and dried. This gave 56 mg (77% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.16min

MS (ES +): m / z = 129 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.78 (br.s, 2 H); 6.42 (dd, 1 H); 7.37-7.43 (m, 1 H); 9.47 (br.s, 1 H ).

Example 268A 3-[(2,6-difluorobenzyl) oxy] -4-fluoropyridine-2-amine

55 mg (0.43 mmol) of 2-amino-4-fluoropyridin-3-ol Examples 267A, 98 mg (0.47 mmol) of 2- (bromomethyl) -1,3-difluorobenzene and 308 mg (0.95 mmol) of cesium carbonate were first placed in 1 ml of anhydrous DMF and heated on an oil bath for 15 min. The temperature was raised to 50 ° C. . The mixture was then filtered and purified by preparative HPLC (Method 9). This gave 70 mg of the title compound (64% of theory).

LC-MS (Method 2): R _t = 0.70min

MS (ES +): m / z = 255 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 5.06 (s, 2 H); 6.04 (br.s, 2 H); 6.42 (dd, 1 H); 7.08-7.16 (m, 2 H); 7.45-7.54 (m, 1 H); 7.62-7.69 (m, 1 H).

Example 269A 8-[(2,6-difluorobenzyl) oxy] -7-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 500 mg (1.97 mmol) of 3-[(2,6-difluorobenzyl) oxy] -4-fluoropyridine-2-amine Example 268A was first placed in 10 ml of ethanol, and 500 mg of 4Å molecular sieve powder and 3.24 g (19.67 mmol) of ethyl 2-chloroacetamidine and the mixture was then heated at reflux for 48 h. All volatile components were evaporated under reduced pressure at 85 ° C. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate = 9/1 isocratic). This gave 368 mg (39% of theory; purity of about 76%) of the title compound.

LC-MS (Method 2): R _t = 1.19min

MS (ES +): m / z = 365 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (t, 3 H); 2.62 (s, 3 H); 4.38 (q, 2 H); 5.60 (s, 2 H); 7.09-7.22 ( m, 3 H); 7.47-7.56 (m, 1 H); 8.98 (dd, 1 H).

Example 270A 8-[(2,6-difluorobenzyl) oxy] -7-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

Add 1.14 ml (1.14 mmol) of a 1N lithium hydroxide solution to 365 mg (0.76 mmol; purity about 76%) of 8-[(2,6-difluorobenzyl) oxy] -7-fluoro-2-methyl In a solution of 16.6 ml of a solution of ethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester 269A in THF / ethanol (5/1), the mixture was stirred at RT overnight. Another 2.67 ml (2.67 mmol) of a 1N lithium hydroxide solution was added and the mixture was stirred at RT overnight. The organic solvent was removed from the reaction mixture under reduced pressure, and the aqueous phase was acidified to pH 4 with 6N hydrochloric acid while cooling with ice water. The formed solid was filtered off and dried under high vacuum. This gave 236 mg of the target compound (87% of theory, 94% purity).

LC-MS (Method 2): R _t = 0.83min

MS (ES +): m / z = 337 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.62 (s, 3 H); 5.60 (s, 2 H); 7.09-7.18 (m, 3 H); 7.47-7.55 (m, 1 H); 9.04 (dd, 1 H); 13.22 (br.s, 1 H).

Example 271A Racemic- (2-cyanobut-2-yl) carbamate

5.00 g (50.94 mmol) of 2-amino-2-methylbutyronitrile [synthesis is described in: Lonza AG, US 5698704 (1997); Deng, SL et al. Synthesis 2001, 2445; Hjorringgaard, CU et al. J Org. Chem. 2009, 74, 1329; Ogrel, A. et al. Eur. J. Org. Chem. 2000, 857] first put 50 ml of THF and 6.5 ml of water, and add 21.83 g (157.92 mmol) at 0 ° ) Of potassium carbonate and 7.9 ml (56.04 mmol) of benzyl chlorocarbonate (benzyl chloroformate). After 8 ml of THF and 3 ml of water were added, the reaction mixture was stirred until overnight while slowly warming to RT. Water was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was dissolved in ether and precipitated with petroleum ether. The product was filtered and the solid was washed with a little petroleum ether and dried under high vacuum. This gave 11.35 g of the target compound (93% of theory, 97% purity).

LC-MS (Method 2): R _t = 0.97min

MS (ES +): m / z = 233 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.95 (t, 3H), 1.51 (s, 3H), 1.75-1.95 (m, 2H), 5.07 (s, 2H), 7.30-7.43 (m, 4H), 7.88-8.03 (m, 1H).

Example 272A Enantio- (2-cyanobut-2-yl) carbamic acid benzyl ester (mirror isomer A)

8 g of racemic- (2-cyanobut-2-yl) carbamic acid benzyl ester Example 271A was separated on the palm phase by a preparative formula to separate into isomers [Column: Daicel Chiralcel OJ-H , 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 20ml / min; 40 ° C, detection: 220nm].

Mirror isomer A: Yield: 3.23 g (> 99% ee)

R _t = 6.69min [Daicel Chiralcel OJ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 273A Enantio- (2-cyanobut-2-yl) carbamic acid benzyl ester (mirror isomer B)

8 g of racemic- (2-cyanobut-2-yl) carbamic acid benzyl example compound 271A was separated on the palm phase by a preparative formula and separated into mirror isomers [column: Daicel Chiralcel OJ- H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol, flow rate: 20ml / min; 40 ° C, detection: 220nm].

Mirror isomer B: Yield: 3.18 g (> 99% ee)

R _t = 8.29min [Daicel Chiralcel OJ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 274A Enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (mirror isomer A)

4.00 g (17.22 mmol) of enantio- (2-cyanobut-2-yl) carbamic acid benzyl ester Example 272A was dissolved in 50 ml of a 7N ammonia methanol solution, 5.33 g of Raney nickel was added and the RT was at 25 bar Under hydrogenation for 24h. The mixture was filtered through celite, the filter cake was washed with methanol and the filtrate was concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 10 / 0.5). This gave 2.20 g of the target compound (54% of theory).

LC-MS (Method 2): R _t = 0.56min

MS (ES +): m / z = 237 (M + H) ⁺

Example 275A Enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (mirror isomer B)

4.00 g (17.22 mmol) of enantio- (2-cyanobut-2-yl) carbamic acid benzyl ester Example 273A was dissolved in 50 ml of a 7N ammonia methanol solution, 5.33 g of Raney nickel was added and the RT was 25 bar Under hydrogenation for 24h. The mixture was filtered through celite, the filter cake was thoroughly washed with methanol, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 10 / 0.5). This gave 3.56 g of the target compound (87% of theory).

LC-MS (Method 13): R _t == 1.40min

MS (ES +): m / z = 237 (M + H) ⁺

Example 276A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -2-methylbut-2-yl} benzyl carbamate (Mirror Isomer A)

2.34 g (6.75 mmol; about 96% purity) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3- Carboxylic acid example 21A, 2.82 g (7.43 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU) and 2.62 g (20.25 mmol) of N, N-diisopropylethylamine were first placed in 43 ml of DMF and stirred at RT for 20 min. Then 1.80 g (7.43 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (Mirror Isomer A) Example 274A was added and the mixture was stirred at RT to Overnight. About 200 ml of water was added and the reaction solution was stirred at RT for 45 min. The formed solid was filtered off, dissolved in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate and washed with a 0.1 N aqueous hydrochloric acid solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 3.55 g of the target compound (96% of theory).

LC-MS (Method 2): R _t = 1.08min

MS (ES +): m / z = 551 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.82 (t, 3H), 1.19 (s, 3H), 1.52-1.63 (m, 1H), 1.75-1.87 (m, 1H), 2.31 (s, 3H), 3.46-3.58 (m, 2H), 5.00 (s, 2H), 5.30 (s, 2H), 6.98 (br.s, 1H), 7.05 (s, 1H), 7.19-7.39 (m, 7H) , 7.54-7.64 (m, 1H), 7.75 (br.s, 1H), 8.48 (s, 1H), [the other signal is hidden under the DMSO signal].

Example 277A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -2-methylbut-2-yl} benzyl carbamate (Mirror Isomer B)

1.40 g (4.03 mmol; purity about 96%) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3- Carboxylic acid example 21A, 1.69 g (4.43 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU) and 1.56 g (12.09 mmol) of N, N-diisopropylethylamine were first placed in 26 ml of DMF and stirred at RT for 20 min. Then 1.00 g (4.23 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (Mirror Isomer B) Example 275A was added and the mixture was stirred at RT overnight . An additional 48 mg (0.20 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (mirror isomer B) was added and the mixture was stirred at RT for 30 min. About 200 ml of water was added, and the reaction solution was stirred at room temperature for 45 min. The formed solid was filtered off and washed twice with water. This gave 2.06 g of the target compound (89% of theory; purity of about 96%). The filter used was washed with acetonitrile and the solvent was concentrated. This gave an additional 0.12 g of the target compound (5% of theory; purity about 96%).

LC-MS (Method 2): R _t = 1.08min

MS (ES +): m / z = 551 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.82 (t, 3H), 1.19 (s, 3H), 1.51-1.63 (m, 1H), 1.75-1.87 (m, 1H), 2.31 (s, 3H), 3.46-3.58 (m, 2H), 5.00 (s, 2H), 5.29 (s, 2H), 6.92 (s, 1H), 7.05 (s, 1H), 7.19-7.39 (m, 7H), 7.54 -7.64 (m, 1H), 7.69 (t, 1H), 8.48 (s, 1H), [Other signals are hidden under the DMSO signal].

Example 278A Enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer A)

282 mg (0.81 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid Example 265A 337 mg (0.89 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU) and 313 mg (2.42 mmol) of N, N-diisopropylethylamine were first placed in 5.1 ml of DMF and stirred at RT for 20 min. Then 219 mg (0.93 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (Mirror Isomer A) Example 274A was added and the mixture was stirred at RT until overnight . A little water / acetonitrile was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 389 mg of the target compound (71% of theory).

LC-MS (Method 2): R _t = 1.14min

MS (ES +): m / z = 569 (M-TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.82 (t, 3H), 1.19 (s, 3H), 1.49-1.62 (m, 1H), 1.76-1.89 (m, 1H), 2.38 (s, 3H), 3.48-3.60 (m, 2H; overlapping with solvent signals), 4.95-5.05 (m, 2H), 5.43 (s, 2H), 7.08 (s, 1H), 7.22-7.43 (m, 7H), 7.64 -7.74 (m, 1H), 8.18 (br.s, 1H), 8.53 (s, 1H), [Other signals are hidden under the DMSO signal].

Example 279A Enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer B)

282 mg (0.81 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid Example 265A 337 mg (0.89 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU) and 313 mg (2.42 mmol) of N, N-diisopropylethylamine were first placed in 5.1 ml of DMF and stirred at RT for 20 min. Then 200 mg (0.85 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (Mirror Isomer B) Example 275A was added and the mixture was stirred at RT overnight. A little water / acetonitrile was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 206 mg of the target compound (36% of theory; purity 97%).

LC-MS (Method 2): R _t = 1.13min

MS (ES +): m / z = 569 (M-TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.82 (t, 3H), 1.19 (s, 3H), 1.49-1.62 (m, 1H), 1.76-1.89 (m, 1H), 2.39 (s, 3H), 3.49-3.61 (m, 2H; overlapping with solvent signals), 4.95-5.05 (m, 2H), 5.44 (s, 2H), 7.08 (s, 1H), 7.23-7.46 (m, 7H), 7.64 -7.74 (m, 1H), 8.20 (br.s, 1H), 8.53 (s, 1H), [Other signals are hidden under the DMSO signal].

Example 280A 5-methoxy-2-nitropyridin-3-ol

1) Under argon, 0.68 ml (4.8 mmol) of trifluoroacetic anhydride was slowly added to a solution of 1.46 g (4.8 mmol) of tetra-n-butylammonium nitrate in 10 ml of dichloromethane, and the mixture was dried at 0 ° Stir for 10 min at ℃.

2) Under argon, in a separate reaction flask, 500 mg (4 mmol) of 5-methoxypyridin-3-ol was dissolved in 10 ml of dichloromethane, and step 1) was added dropwise at -30 ° C. Its solution. The reaction mixture was stirred in a melting ice bath (not higher than 0 ° C) for 4 h. Diatomaceous earth was added to the reaction solution, the mixture was concentrated at a relatively low temperature and the product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate: 9/1). This gave 637 mg (94% of theory) of the target compound.

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 171 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 3.90 (s, 3 H), 7.11 (d, 1 H), 7.78 (d, 1 H), 11.35 (br. 1 H).

Example 281A 3-[(2,6-difluorobenzyl) oxy] -5-methoxy-2-nitropyridine

0.93 g (4.47 mmol) of 2,6-difluorobenzyl bromide was added to 0.76 g (4.47 mmol) of 5-methoxy-2-nitropyridin-3-ol from Example 280A and 2.18 g (6.70 mmol) 12.5 ml of cesium carbonate in DMF solution, and the mixture was stirred at RT overnight. The reaction mixture was added to 100 ml of a 1N aqueous hydrochloric acid solution and stirred at RT for 30 minutes. The solid was filtered off, washed with water and dried under high vacuum. This gave 1.28 g (97% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 297 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 4.00 (s, 3 H), 5.42 (s, 2 H), 7.21 (t, 2 H), 7.58 (Five-fold peak, 1 H), 7.70 (d, 1 H), 7.88 (d, 1 H).

Example 282A 3-[(2,6-difluorobenzyl) oxy] -5-methoxypyridin-2-amine

0.73 g (13.1 mmol) of iron powder was added to 1.25 g (4.22 mmol) of 3-[(2,6-difluorobenzyl) oxy] -5-methoxy-2-nitropyridine from Example 281A 12.7 ml of ethanol solution, and the mixture was heated under reflux. Slowly, 3.23 ml (38.8 mmol) of a concentrated aqueous hydrochloric acid solution was added dropwise, and the mixture was stirred at reflux for another 30 min. The reaction was cooled and stirred into an ice / water mixture and stirred for 30 min. The organic solvent was removed under reduced pressure, the aqueous phase was made alkaline with a 1N aqueous sodium hydroxide solution and stirred with dichloromethane and the mixture was filtered through celite. The filter cake was washed with dichloromethane and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was dried under high vacuum. This gave 974 mg of the target compound (85% of theory).

LC-MS (Method 2): R _t = 0.61min

MS (ES +): m / z = 267 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 3.72 (s, 3 H), 5.10 (s, 2 H), 5.14 (s, 2 H), 7.04 (d, 1 H), 7.20 (t , 2 H), 7.32 (d, 1 H), 7.55 (pentaplex, 1 H).

Example 283A 8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

0.93 g of 3Å molecular sieve powder and 6.0 g (36.43 mmol) of ethyl 2-chloroacetamidoacetate were added to 0.97 g (3.64 mmol) of 3-[(2,6-difluorobenzyl) oxy from Example 282A Group] -5-methoxypyridin-2-amine and the mixture was heated to reflux overnight. The reaction mixture was concentrated on a dry ice rotary evaporator at a water bath temperature of 85 ° C. The crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate: 9/1 isocratic). This gave 583 mg of the target compound (41% of theory).

LC-MS (Method 2): R _t = 1.09min

MS (ES +): m / z = 377 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.36 (t, 3 H), 2.54 (s, 3 H; hidden by DMSO signal), 3.83 (s, 3 H), 4.37 (q, 2 H ), 5.32 (s, 2 H), 7.05 (d, 1 H), 7.23 (t, 2 H), 7.60 (quintese peak, 1 H), 8.58 (d, 1 H).

Example 284A 8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

Add 7.7 ml of a 1 M aqueous lithium hydroxide solution to 580 mg (1.54 mmol) 33-THF of 8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 283A / Methanol (5/1) solution, and the mixture was stirred at 40 ° C overnight. The reaction mixture was cooled, adjusted to pH 4 using 6N aqueous hydrochloric acid and then cooled with ice and then the organic solution was removed on a rotary evaporator. The formed solid was filtered off, washed with water and then dried under high vacuum to thereby obtain 507 mg of the target compound (94% of theory).

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 349 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.54 (s, 3 H; overlaps with DMSO signal), 3.85 (s, 3 H), 5.38 (s, 2 H), 7.20-7.32 (m, 3 H), 7.61 (fivefold, 1 H), 8.68 (d, 1 H), 13.40 (br.s, 1 H).

Example 285A Racemic- (2-cyanopentanol-2-yl) carbamate

76.4 g (552.7 mmol) of potassium carbonate was added to 20 g (178.3 mmol) of racemic-2-amino-2-methylvaleronitrile (described in: Deng, SL. Et al., Synthesis 2001, 2445-2449 Freifelder, M. et al., J. Am. Chem. Soc. 1960, 696-698) and 2.631 in THF / water (8/1). 27.6 ml (196.1 mmol) of benzyl chloroformate were slowly added dropwise at 0 ° C, and the mixture was stirred at RT overnight. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 4/1). This gave 43.84 g of the target compound (76% of theory, 76% purity).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 247 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.90 (t, 3H), 1.31-1.48 (m, 2H), 1.52 (s, 3H), 1.70-1.88 (m, 2H), 5.07 (s , 2H), 7.30-7.42 (m, 5H), 8.00 (br.s, 1H).

Example 286A Enantio- (2-cyanopent-2-yl) carbamate benzyl ester (mirror isomer A) from 285A

43.8 g (135.3 mmol) of the racemic- (2-cyanopent-2-yl) carbamic acid benzyl ester from Example 285A were separated into the mirror isomers by preparative separation on the counter phase [column : SFC Chiralpak AZ-H, 5 μm, 250 × 50 mm, mobile phase: 85% CO ₂ , 15% methanol, flow rate: 250 ml / min; temperature: 28 ° C., back pressure: 100 bar, detection: 220 nm].

Mirror isomer A: Yield: 13.13 g (> 99% ee)

R _t = 2.76min [SFC Chiralpak AZ-H, 5μm, 250 x 4.6mm; mobile phase: 90% CO ₂ , 10% methanol; flow rate: 3ml / min; detection: 220nm].

Example 287A Enantio- (2-cyanopent-2-yl) carbamic acid benzyl ester (mirror isomer B) from 285A

43.8 g (135.3 mmol) of the racemic- (2-cyanopent-2-yl) carbamic acid benzyl ester from Example 285A were separated into the mirror isomers by preparative separation on the counter phase [column : SFC Chiralpak AZ-H, 5 μm, 250 × 50 mm, mobile phase: 85% CO ₂ , 15% methanol, flow rate: 250 ml / min; temperature: 28 ° C., back pressure: 100 bar, detection: 220 nm].

Mirror isomer B: Yield: 13.48 g (about 90.4% ee)

R _t = 3.93min [SFC Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 90% CO ₂ , 10% methanol; flow rate: 3ml / min; detection: 220nm].

Example 288A Enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester (mirror isomer A)

13.1 g (53.31 mmol) of benzyl enantio- (2-cyanopentane-2-yl) carbamate (mirror isomer A) VAK5346-1-3 from Example 286A was dissolved in 155 ml of a 7N ammonia methanol solution , And added 16.5 g of Raney nickel (50% concentration suspension solution) under argon. The reaction mixture was hydrogenated in an autoclave at 20-30 bar until overnight. The mixture was filtered through celite, the filter cake was washed with methanol, dichloromethane / 2N ammonia methanol solution (20/1), and the filtrate was concentrated. The residue was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 40/1 to 20/1). This gave 9.85 g of the target compound (63% of theory, 86% purity).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 251 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.83 (t, 3H), 1.11 (s, 3H), 1.15-1.24 (m, 2H), 1.37 (br.s, 2H), 1.42-1.51 (m, 1H), 1.53-1.63 (m, 1H), 2.46 (d, 1H), 2.66 (d, 1H), 4.97 (s, 2H), 6.69 (br.s, 1H), 7.26-7.40 (m , 5H).

Example 289A Enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester (mirror isomer B)

13.5 g (54.73 mmol) of benzyl enantio- (2-cyanopentane-2-yl) carbamate (mirror isomer) VAK5347-1-4 from Example 287A was dissolved in 159 ml of a 7N ammonia methanol solution And 16.95 g of Raney Nickel (50% suspension solution) were added under argon. The reaction mixture was hydrogenated in an autoclave at 20-30 bar until overnight. The mixture was filtered through celite, followed by methanol, The filter cake was washed with dichloromethane / 2N ammonia methanol solution (10/1), and the filtrate was concentrated. The residue was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 40/1 to 20/1). This gave 9.46 g of the target compound (61% of theory, 88% purity).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 251 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.83 (t, 3H), 1.11 (s, 3H), 1.15-1.24 (m, 2H), 1.37 (br.s, 2H), 1.42-1.51 (m, 1H), 1.53-1.63 (m, 1H), 2.46 (d, 1H), 2.66 (d, 1H), 4.97 (s, 2H), 6.69 (br.s., 1H), 7.26-7.40 ( m, 5H).

Example 290A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -2-methylpent-2-yl} benzyl carbamate trifluoroacetate (mirror isomer B)

Add 156 mg (0.41 mmol) of HATU and 0.28 ml (1.58 mmol) of N, N-diisopropylethylamine to 110 mg (0.32 mmol) of 8-[(2,6-difluorobenzyl) from Example 284A ) Oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid. The reaction mixture was stirred at RT for 10 min, and then 103 mg (0.41 mmol) of the enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester (Example isomer B) The mixture was stirred at RT for 1 hour. TFA was added to the reaction mixture, which was then separated by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 180 mg of the target compound (82% of theory).

LC-MS (Method 2): R _t = 1.15min

MS (ES +): m / z = 581 (M-TFA + H) ⁺

Example 291A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -2-methylbut-2-yl} benzyl carbamate trifluoroacetate (mirromeric isomer A)

Add 156 mg (0.41 mmol) of HATU and 0.28 ml (1.58 mmol) of N, N-diisopropylethylamine to 110 mg (0.32 mmol) of 8-[(2,6-difluorobenzyl) from Example 284A ) Oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid. The reaction mixture was stirred at RT for 10 min, and then 97 mg (0.41 mmol) of the enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester from Example 274A (mirromeric isomer A) was added. The mixture was stirred at RT for 45 min. TFA was added to the reaction mixture, which was then separated by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 157 mg of the target compound (73% of theory).

LC-MS (Method 2): R _t = 1.09min

MS (ES +): m / z = 567 (M-TFA + H) ⁺

Example 292A Enantiomer- {1-[({6-Bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] -2-methylpent-2-yl} carbamate benzyl trifluoroacetate (mirror isomer B)

Add 2.57 g (7.99 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 4 ml (36.31 mmol) of 4-methylmorpholine to 2.88 g (7.26 mmol) 6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 19A. Then 2.0 g (7.99 mmol) of the enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester from Example 289A (mirror isomer B) was added and the reaction mixture was allowed to react at RT Stir for 1 hour. 200 ml of water was added to the reaction solution, and the formed solid was stirred for about 30 min, filtered, washed with water and dried under high vacuum. This gave 4.41 g of the target compound (73% of theory, 76% purity).

LC-MS (Method 2): R _t = 1.38min

MS (ES +): m / z = 629 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.85 (t, 3H), 1.19 (s, 3H), 1.23-1.34 (m, 2H), 1.44-1.54 (m, 1H), 1.71-1.80 (m, 1H), 2.53 (s, 3H), 3.47-3.59 (m, 2H), 5.00 (s, 2H), 5.38 (s, 2H), 7.08 (br.s., 1H), 7.21-7.37 ( m, 7H), 7.40 (s, 1H), 7.56-7.66 (m, 1H), 7.91-7.98 (m, 1H), 8.83 (s, 1H).

Example 293A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methyl-6- (morpholinolin-4-yl) imidazo [1,2-a ] Pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer B)

Under argon, 1.7 ml of toluene (anhydrous) was added to 50 mg (0.07 mmol) of the enantiomer-{1-[({6-bromo-8-[(2,6-difluorobenzyl)) from Example 292A. Oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror Isomer B), 0.02 ml (0.20 mmol) of morpholine, 9 mg (0.09 mmol) of sodium tert-butoxide, 2.5 mg (0.003 mmol) of tris (dibenzylideneacetone) dipalladium, and 3.8 mg ( 0.008 mmol) in dicyclohexyl [2 ', 4', 6'-tris (prop-2-yl) biphenyl-2-yl] fluorene [X-PHOS], and the mixture was stirred at 100 ° C overnight. The reaction solution was concentrated and the residue was treated in dichloromethane and washed twice with water. The organic phase was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product was treated again in dichloromethane and washed once with a saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The product fraction was then purified by thin layer chromatography (mobile phase: dichloromethane / methanol = 20/1). This gave 11 mg of the target compound (26% of theory).

LC-MS (Method 2): R _t = 1.09min

MS (ES +): m / z = 636 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.85 (t, 3H), 1.20 (s, 3H), 1.23-1.34 (m, 2H), 1.45-1.58 (m, 1H), 1.69-1.79 (m, 1H), 2.50 (s, 3H below solvent peak), 3.05 (t, 4H), 3.48-3.54 (m, 2H), 3.76 (t, 4H), 4.99 (s, 2H), 5.32 (s, 2H), 7.02-7.08 (m, 2H), 7.20-7.27 (m, 2H), 7.28-7.37 (m, 5H), 7.54-7.66 (m, 2H), 8.16-8.21 (m, 1H).

Example 294A Enantiomer- {1-[({6-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -2-methylpent-2-yl} benzyl carbamate trifluoroacetate (mirror isomer B)

Under argon, 50 mg (0.07 mmol) of the enantiomer- {1-[({6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazole) from Example 292A was first added. Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer B), 7.5 mg ( 0.09 mmol) of cyclopropylboronic acid, 57 mg (0.27 mmol) of potassium phosphate, 3 mg (0.01 mmol) of tricyclohexylphosphine, and 1.2 mg (0.005 mmol) of palladium (II) acetate, and 0.6 ml of toluene / water was added 20/1. Argon was passed through the reaction mixture for 5 min, and the reaction mixture was stirred at 100 ° C overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 27 mg of the target compound (56% of theory).

LC-MS (Method 2): R _t = 1.20min

MS (ES +): m / z = 591 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.80-0.92 (m, 6H), 1.02 (d, 2H), 1.22 (s, 3H), 1.24-1.36 (m, 3H), 1.44-1.58 (m, 1H), 1.73-1.82 (m, 1H), 2.03-2.15 (m, 1H), 2.55 (br.s., 3H), 3.50-3.62 (m, 2H), 5.01 (s, 2H), 5.44 (br.s., 2H), 7.08 (br.s., 1H), 7.22-7.41 (m, 9H), 7.62 (quin, 1H), 8.54 (s, 1H).

Example 295A Racemic-2-amino-3-fluoro-2-methylpropionitrile

The title compound is known from the literature: McCaathy, J. et al., Journal of Medicinal Chemistry 2002, 45, 2240-2249.

Bergmann, E.D., et al., Journal of the Chemical Society 1963, 3462-3463.

Another method:

1.0 g (0.94 ml; 13.15 mmol) of fluoroacetone was first put into 11 ml of a 2N ammonia methanol solution. At RT, 721 mg (14.72 mmol) of sodium cyanide and 788 mg (14.72 mmol) of ammonium chloride were continuously added, and the mixture was stirred under reflux for 2 hours. The reaction solution was cooled, filtered and washed with dichloromethane. A solid precipitated from the mother liquor. This solid was filtered. Dichloromethane and methanol were removed from the mother liquor by distillation under reduced pressure. Thus, 1.32 g of the target compound was obtained (89% of the theoretical value and purity of about 90%). The product was used in the next reaction without further purification.

GC-MS (Method 14): R _t = 1.64min

MS (EIpos): m / z = 87 (M-CH ₃ ) ⁺

Example 296A Racemic- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl ester

5.07 g (36.67 mmol) of potassium carbonate was added to 1.34 g (11.83 mmol, about 90% purity) of racemic-2-amino-3-fluoro-2-methylpropionitrile from Example 295A in 29 ml of THF / Water (9/1) solution. At 0 ° C, 1.69 ml (11.83 mmol) of benzyl chloroformate were slowly added dropwise, and the reaction mixture was stirred at RT overnight. The solvent was decanted and the aqueous phase was extracted with THF. This was followed by decantation of THF. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was separated by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 7 / 3-9 / 1) and the product fractions were concentrated on a rotary evaporator. This gave 1.89 g of the target compound (66% of theory; purity 97%).

LC-MS (Method 2): R _t = 0.89min

MS (ES +): m / z = 237 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.58 (d, 3H), 4.47-4.78 (m, 2H), 5.10 (s, 2H), 7.30-7.43 (m, 5H), 8.34 (br .s, 1H).

Example 297A Enantio- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl ester (mirror isomer A)

3.0 g (12.69 mmol) of the racemic- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl ester from Example 296A was separated on the palm phase by preparative separation into mirror isomers. [Column: Daicel Chiralpak AY-H, 5 μm, 250 × 20 mm, mobile phase: 80% isohexane, 20% isopropanol, flow rate: 15 ml / min; 40 ° C., detection: 220 nm].

Mirror isomer A: Yield: 1.18 g (> 99% ee)

R _t = 5.37min [Daicel Chiralcel AY-H, 5μm, 250 × 4.6mm; mobile phase: 70% isohexane, 30% 2-propanol; flow rate 1.0ml / min; 40 ° C; detection: 220nm].

Example 298A Enantio- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl ester (mirror isomer B)

3.0 g (12.69 mmol) of the racemic- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl ester from Example 296A was separated on the palm phase by preparative separation into mirror isomers. [Column: Daicel Chiralpak AY-H, 5 μm, 250 × 20 mm, mobile phase: 80% isohexane, 20% isopropanol, flow rate: 15 ml / min; 40 ° C., detection: 220 nm].

Mirror isomer B: Yield: 1.18 g (> 99% ee)

R _t = 6.25min [Daicel Chiralcel AY-H, 5μm, 250 × 4.6mm; mobile phase: 70% isohexane, 30% 2-propanol; flow rate 1.0ml / min; 40 ° C; detection: 220nm].

Example 299A Racemic- (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid benzyl ester

Under argon, 1.55 g of Raney nickel (suspension solution) was added to 1.2 g (5.08 mmol) of racemic- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl from Example 296A. 14.9 ml of a 7N ammonia methanol solution, and the mixture was hydrogenated at about 25 bar hydrogen pressure and RT for 24 hours. The reaction mixture was filtered through celite, the filter cake was washed with methanol and the filtrate was concentrated. This gave 1.2 g of the target compound (98% of theory).

LC-MS (Method 2): R _t = 0.49min

MS (ES +): m / z = 241 (M + H) ⁺

Example 300A Enantio- (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid benzyl ester (mirror isomer A)

Under argon, 1.55 g of Raney nickel (suspension solution) was added to 1.2 g (5.08 mmol) of the enantio- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl from Example 297A. The ester (mirror isomer A) in 14.9 ml of a 7N ammonia methanol solution, and the mixture was hydrogenated at about 25 bar hydrogen pressure and RT for 24 hours. The reaction mixture was filtered through celite, the filter cake was washed with methanol and the filtrate was concentrated. This gave 700 mg of the target compound (57% of theory; purity 85%).

LC-MS (Method 2): R _t = 0.52min

MS (ES +): m / z = 241 (M + H) ⁺

Example 301A Enantio- (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid benzyl ester (mirror isomer B)

Under argon, 1.55 g of Raney nickel (suspension solution) was added to 1.2 g (5.08 mmol) of the enantio- (2-cyano-1-fluoroprop-2-yl) carbamic acid benzyl from Example 298A The ester (mirror isomer A) in 14.9 ml of a 7N ammonia methanol solution, and the mixture was hydrogenated at about 25 bar hydrogen pressure and RT for 24 hours. The reaction mixture was filtered through celite, the filter cake was washed with methanol and the filtrate was concentrated. This gave 1.2 g of the target compound (98% of theory; purity 85%).

LC-MS (Method 2): R _t = 0.50min

MS (ES +): m / z = 241 (M + H) ⁺

Example 302A Racemic- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] -3-fluoro-2-methylprop-2-yl} benzyl carbamate

Under argon, 147 mg (0.44 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- from Example 21A 3-carboxylic acid, 185 mg (0.49 mmol) of HATU and 0.31 ml (1.77 mmol) of N, N-diisopropylethylamine were stirred in 7 ml of DMF for 20 min, then 112 mg (0.39 mmol) of Racemic benzyl- (1-amino-3-fluoro-2-methylprop-2-yl) carbamate and the mixture was stirred at RT overnight. Water / TFA was added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.05% formic acid). The product fractions were concentrated on a rotary evaporator. This gave 56 mg of the target compound (23% of theory).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 555 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.25-1.29 (m, 3H), 2.32 (s, 3H), 3.53-3.65 (m, 2H), 4.45-4.56 (m, 1H), 4.57 -4.69 (m, 1H), 5.02 (s, 2H), 5.31 (s, 2H), 7.02 (br.s, 1H), 7.20-7.27 (m, 2H), 7.28-7.38 (m, 5H), 7.55 -7.65 (m, 1H), 7.89 (br.s, 1H), 8.46 (s, 1H), [additional signal under solvent peak].

Example 303A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3-fluoro-2-methylprop-2-yl} benzyl carbamate trifluoroacetate (mirror isomer A)

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 180 mg (0.47 mmol) of HATU and 0.24 ml (1.35 mmol) of N, N-diisopropylethylamine were stirred in 2.9 ml of DMF for 20 min, and then 134 mg (0.47 mmol, 85% purity) from Example 300A was added Enantio- (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid benzyl ester (mirromeric isomer A) and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 148 mg of the target compound (47% of theory).

LC-MS (Method 2): R _t = 1.03min

MS (ES +): m / z = 555 (M-TFA + H) ⁺

Example 304A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3-fluoro-2-methylprop-2-yl} benzyl carbamate trifluoroacetate (mirror isomer B)

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 180 mg (0.47 mmol) of HATU and 0.24 ml (1.35 mmol) of N, N-diisopropylethylamine were stirred in 2.9 ml of DMF for 20 min, and then 134 mg (0.47 mmol, 85% purity) from Example 301A was added. Enantio- (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid benzyl ester (mirror isomer B) and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 201 mg of the target compound (67% of theory).

LC-MS (Method 2): R _t = 1.04min

MS (ES +): m / z = 555 (M-TFA + H) ⁺

Example 305A Enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamic acid trifluoroacetate benzyl ester (mirromeric isomer A)

150 mg (0.43 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylate from Example 265A Acid, 171 mg (0.45 mmol) of HATU and 0.22 ml (1.29 mmol) of N, N-diisopropylethylamine were stirred in 2.7 ml of DMF for 20 min, then 127 mg (0.45 mmol, 85% purity) was added from the example 300A benzyl enanti- (1-amino-3-fluoro-2-methylprop-2-yl) carbamate (mirror isomer A) and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 170 mg of the target compound (50% of theory, 87% purity).

LC-MS (Method 2): R _t = 1.05min

MS (ES +): m / z = 573 (M-TFA + H) ⁺

Example 306A Enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamic acid trifluoroacetate benzyl ester (mirromeric isomer B)

150 mg (0.43 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylate from Example 265A Acid, 171 mg (0.45 mmol) of HATU and 0.22 ml (1.29 mmol) of N, N-diisopropylethylamine were stirred in 2.7 ml of DMF for 20 min, then 127 mg (0.45 mmol, 85% purity) was added from the example 301A benzyl enantiomer- (1-amino-3-fluoro-2-methylprop-2-yl) carbamate (mirror isomer B) and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 202 mg of the target compound (60% of theory, 96% purity).

LC-MS (Method 2): R _t = 1.06min

MS (ES +): m / z = 573 (M-TFA + H) ⁺

Example 307A 8-[(2,6-difluorobenzyl) oxy] -2-methyl-6-vinylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 1.0 g (2.35 mmol) of 6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] from Example 18A Pyridine-3-carboxylic acid ethyl ester, 945 mg (7.06 mmol) of potassium vinyl trifluoroborate, 1.64 ml (11.76 mmol) of triethylamine, and 388 mg (0.48 mmol) of dichloro [1,1'-ferrocene Bis (biphenylphosphine)] palladium (II), dichloromethane were first put into 50 ml of 2-propanol, and the mixture was stirred at 90 ° C for 30 minutes. The reaction mixture was cooled, ethyl acetate was added and the mixture was washed three times with water and once with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered, concentrated and dried under high vacuum. This gave 876 mg of the target compound (quantitative yield). This product was used in subsequent reactions without further purification.

LC-MS (Method 2): R _t = 1.20min

MS (ES +): m / z = 373 (M + H) ⁺

Example 308A 8-[(2,6-difluorobenzyl) oxy] -6-methylamido-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Add 1.45 ml (0.24 mmol, 4% strength aqueous solution) of osmium tetroxide and 1.52 g (7.13 mol) of sodium periodate to 876 mg (2.35 mmol) of 8-[(2,6-difluoro) from Example 307A Benzyl) oxy] -2-methyl-6-vinylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester in 20 ml of a THF / water (1/1) solution, and the mixture Stir at RT for 1 h. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with water and once with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate gradient). This gave 478 mg of the target compound (54% of theory).

LC-MS (Method 2): R _t = 1.12min

MS (ES +): m / z = 375 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.39 (t, 3H), 2.60 (s, 3H), 4.41 (q, 2H), 5.40 (s, 2H), 7.20-7.28 (m, 2H ), 7.42 (s, 1H), 7.55-7.65 (m, 1H), 9.54 (s, 1H), 10.06 (s, 1H).

Example 309A 8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 0.50 ml (3.77 mmol) of diethylaminosulfur trifluoride was added dropwise to 235 mg (0.63 mmol) of the 8-[(2,6-difluorobenzyl) oxy group from Example 308A ] -6-Methylmethyl-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester in 4 ml of anhydrous dichloromethane, and the mixture was stirred at RT overnight. The reaction mixture was cooled in an ice bath, a saturated aqueous sodium bicarbonate solution was carefully added and the formed phases were separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 249 mg of the target compound (quantitative yield).

LC-MS (Method 2): R _t = 1.19min

MS (ES +): m / z = 397 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (t, 3H), 2.58 (s, 3H), 4.38 (q, 2H), 5.39 (s, 2H), 7.11-7.40 (m, 4H ), 7.55-7.66 (m, 1H), 9.17-9.21 (m, 1H).

Example 310A 8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid

45 mg (1.87 mmol) of lithium hydroxide was added to 247 mg (0.62 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methyl from Example 309A The imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester in 6 ml of THF / methanol (5/1), and then the reaction mixture was stirred at RT overnight. Dichloromethane and water were added to the reaction mixture, separation was performed and the aqueous phase was acidified with 1N hydrochloric acid. The precipitate was filtered, washed with water and dried under high vacuum overnight. This gave 202 mg of the target compound (88% of theory).

LC-MS (Method 2): R _t = 0.89min

MS (ES +): m / z = 369 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.57 (s, 3H), 5.38 (s, 2H), 7.10-7.41 (m, 4H), 7.55-7.65 (m, 1H), 9.24 (s , 1H), 13.38 (s, 1H).

Example 311A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester (mirror isomer A)

Add 126 mg (0.33 mmol) HATU and 0.24 ml (1.38 mml) of N, N-diisopropylethylamine to 102 mg (0.28 mmol) of 8-[(2,6-difluorobenzyl) ) Oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid, and the mixture was stirred at room temperature for 10 minutes. Then 98 mg (0.41 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester (mirror isomer A) from Example 274A was added to the reaction solution, and the mixture was added Stir at RT overnight and then purify the product by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 124 mg of the target compound (77% of theory).

LC-MS (Method 2): R _t = 1.23min

MS (ES +): m / z = 587 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.82 (t, 3H), 1.19 (s, 3H), 1.49-1.61 (m, 1H), 1.77-1.87 (m, 1H), 3.49-3.60 (m, 2H), 5.00 (s, 2H), 5.37 (s, 2H), 7.01-7.10 (m, 1H), 7.13-7.38 (m, 9H), 7.55-7.65 (m, 1H), 7.89 (t 1H), 8.98 (s, 1H).

Example 312A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer B)

Add 126 mg (0.33 mmol) of HATU and 0.24 ml (1.38 mml) of N, N-diisopropylethylamine to 102 mg (0.28 mmol) of 8-[(2,6-difluorobenzyl) from Example 310A ) Oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid, and the mixture was stirred at room temperature for 10, and then 103 mg (0.41 mmol) ) Enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester (Mirror isomer B) from Example 289A was added to the reaction solution, and the mixture was stirred at RT until overnight and then The product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 123 mg of the target compound (74% of theory).

LC-MS (Method 2): R _t = 1.31min

MS (ES +): m / z = 601 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.85 (t, 3H), 1.20 (s, 3H), 1.23-1.34 (m, 2H), 1.44-1.57 (m, 1H), 1.68-1.82 (m, 1H), 3.49-3.58 (m, 2H), 4.99 (s, 2H), 5.37 (s, 2H), 7.01-7.38 (m, 10H), 7.55-7.65 (m, 1H), 7.90 (t 1H), 8.98 (s, 1H).

Example 313A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer A)

50 mg (0.14 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine from Example 310A 3-carboxylic acid, 54 mg (0.14 mmol) of HATU and 0.07 ml (0.41 mmol) of N, N-diisopropylethylamine in 0.9 ml of DMF solution and stirred for 20 min, then 40 mg (0.14 mmol, 85%) was added ) Enantio- (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid benzyl ester from Example 300A (Mirror Isomer A) and the mixture was stirred at RT overnight. Water / THF was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 75 mg of the target compound (78% of theory).

LC-MS (Method 2): R _t = 1.19min

MS (ES +): m / z = 591 (M-TFA + H) ⁺

Example 314A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer B)

50 mg (0.14 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine from Example 310A 3-carboxylic acid, 54 mg (0.14 mmol) of HATU and 0.07 ml (0.41 mmol) of N, N-diisopropylethylamine in 0.9 ml of a DMF solution, stirred for 20 min, and then added 40 mg (0.14 mmol, 85 %) Enantio-benzyl (1-amino-3-fluoro-2-methylprop-2-yl) carbamic acid (Mirror Isomer B) from Example 301A and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 47 mg of the target compound (44% of theory, purity 89%).

LC-MS (Method 2): R _t = 1.20min

MS (ES +): m / z = 591 (M-TFA + H) ⁺

Example 315A N ^2- (third butoxycarbonyl) -N ⁶ -({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridine-3-yl} carbonyl) -L-lysine methyl trifluoroacetate

300 mg (0.90 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 377 mg (1.17 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 0.5 ml (4.51 mmol) of 4-methylmorpholine were first placed in 5.75 ml In DMF, the mixture was stirred at room temperature for 10 min, then 318 mg (0.99 mmol) of N ^2- (third butoxycarbonyl) -L-lysine methyl acetate was added and the mixture was stirred at RT overnight. Another 188 mg (0.59 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate, 0.4 ml (3.61 mmol) of 4-methylmorpholine and 376 mg (1.17 mmol) of N ^2- (third butoxycarbonyl) -L-lysine methyl acetate to the reaction solution, and the mixture was stirred at room temperature overnight. Water / TFA was added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 205 mg of the target compound (33% of theory).

LC-MS (Method 2): R _t = 0.95min

MS (ES +): m / z = 575 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.30-1.43 (m, 13H), 1.48-1.72 (m, 2H), 2.41 (s, 3H), 2.54 (s, 3 H; signal by DMSO Covert), 3.30 (q, 2H), 3.61 (s, 3H), 3.91-3.98 (m, 1H), 5.40 (s, 2H), 7.01 (s, 1H), 7.13 (s, 1H), 7.22-7.30 (m, 2H), 7.57-7.66 (m, 1H), 8.50-8.55 (m, 1H).

Example 316A Racemic-2-amino-3- (4-fluorophenyl) -2-methylpropionitrile

1.0 g (6.57 mmol) of 4-fluorophenylacetone was first placed in 13.1 ml of a 2N ammonia methanol solution, 361 mg (7.36 mmol) of sodium cyanide and 877 mg (7.36 mmol) of ammonium chloride were added and the mixture was Stir under reflux for 2 hours. The reaction solution was cooled and diluted with 20 ml of dichloromethane, and the precipitated solid was filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (RP18 column, mobile phase: cyclohexane / ethyl acetate 4/1 to 1/1). This gave 340 mg of the target compound (23% of theory, 81% purity).

LC-MS (Method 15): R _t = 1.87min

MS (ES +): m / z = 179 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.30 (s, 3H), 2.87 (q, 2H), 7.13-7.20 (m, 2H), 7.28-7.36 (m, 2H).

Example 317A Racemic-3- (4-fluorophenyl) -2-methylpropan-1,2-diamine

340 mg (1.54 mmol, purity about 81%) of racemic-2-amino-3- (4-fluorophenyl) -2-methylpropionitrile from Example 316A was dissolved in 2 ml of ethanol, and 4.6 ml was added (4.64 mmol) of 1N hydrochloric acid in ethanol. 5.2 mg (0.02 mmol) of platinum (IV) oxide was added and the reaction mixture was hydrogenated at 3 bar for 5 hours. An additional 5 mg (0.02 mmol) of platinum (IV) oxide was added to the reaction solution, and the mixture was hydrogenated at 3 bar for 5 hours. The mixture was then filtered through celite, 1.5 ml (3.09 mmol) of a 2N solution of hydrochloric acid in ether was added to the filtrate, the mixture was concentrated and the product was dried under high vacuum. The product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution 60/1 to 20/1). This gave 145 mg of the target compound (51% of theory).

LC-MS (Method 13): R _t = 0.20min

MS (ES +): m / z = 183 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.80 (s, 3H), 1.34 (br.s., 4H), 2.24-2.34 (m, 2H), 2.53 (d, 2H), 7.03- 7.12 (m, 2H), 7.18-7.27 (m, 2H).

Example 318A Racemic-2-amino-2-methyl-3- (pyridin-2-yl) propionitrile

Put 4.88 ml (14.80 mmol) of 1- (pyridin-2-yl) acetone into 29.6 ml of 2N ammonia methanol solution, add 812 mg (16.57 mmol) of sodium cyanide and 1.97 g (16.57 mmol) of chlorinated Ammonium and the mixture was stirred at reflux for 2 hours. The reaction mixture was cooled and diluted with dichloromethane, and the resulting solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate = 1/1). The impure product fraction was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 1/1). This gave a total of 1.1 g of the target compound (45% of theory).

LC-MS (Method 15): R _t == 1.30min

MS (ES +): m / z = 162 (M + H) ⁺

Example 319A Racemic-2-methyl-3- (pyridin-2-yl) propan-1,2-diamine trihydrochloride

666 mg (4.01 mmol) of 2-amino-2-methyl-3- (pyridin-2-yl) propionitrile from Example 318A was first placed in 41 ml of THF, and 2.61 ml was slowly added under 0 ° C argon (2.61 mmol) of a 1N lithium aluminum hydride in THF. The reaction mixture was stirred at 0 ° C. Stir for 30 min and overnight at RT. Then another 0.7 ml (0.70 mmol) of a 1N lithium aluminum hydride in THF solution was added, and the mixture was stirred at RT for 2 hours. The reaction mixture was cooled to 0 ° C, and 0.4 ml of water, 0.4 ml of a 2N aqueous sodium hydroxide solution, and 0.8 ml of water were added. The precipitate was filtered and washed with dichloromethane / methanol (10/1). A 2N solution of hydrogen chloride in ether was added to the filtrate, and the product was dried under high vacuum. This gave 1.15 g of the target compound (104% of theory).

LC-MS (Method 15): R _t = 1.26min

MS (ES +): m / z = 166 (M-3HCl + H) ⁺

Example 320A Racemic-4-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 94 mg (0.25 mmol) of HATU and 0.2 ml (1.13 mmol) of N, N-diisopropylethylamine in 1.4 ml of a DMF solution were stirred for 20 min. 64 mg (0.27 mmol) of 4-amino-3,3 was added -Difluoropiperidine-1-carboxylic acid tert-butyl ester and then the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the precipitated solid was stirred at room temperature for 30 min, filtered, washed with water and dried under high vacuum. This gave 81 mg of the target compound (65% of theory).

LC-MS (Method 2): R _t == 1.06min

MS (ES +): m / z = 551 (M + H) ⁺

Example 321A 5-methyl-2-nitropyridin-3-ol

Under ice cooling, 25 g (0.23 mol) of 5-methylpyridin-3-ol was first placed in 226 ml (4.12 mol) of concentrated sulfuric acid, and then the mixture was warmed to RT. Once the starting material was completely dissolved, the reaction mixture was cooled to 0 ° C again. From 0 ° C to 10 ° C, 14.25 ml (0.34 mol) of fuming nitric acid was slowly added dropwise over a period of 3.5 hours. The mixture was warmed to 15 ° C and then the mixture was stirred at RT overnight. The reaction solution was poured into 1000 g of ice and extracted twice with 500 ml of ethyl acetate each time. The combined organic phases were dried and concentrated. This gave 31.5 g of the target compound (89% of theory).

LC-MS (Method 13): R _t = 1.21min

MS (ES +): m / z = 155 (M + H) ⁺

Example 322A 3-[(2,6-difluorobenzyl) oxy] -5-methyl-2-nitropyridine

31.5 g (0.155 mol) of 5-methyl-2-nitropyridin-3-ol from Example 321A and 75.78 g (0.23 mol) of cesium carbonate were first put into 432 ml of DMF, and 33.7 g (0.163 mol) of 2,6-difluorobenzyl bromide and the mixture was stirred at RT overnight. The reaction solution was stirred into 3600 ml of a 0.5 N aqueous hydrochloric acid solution. Stir the formed precipitate for another 30min and evacuate Filter, wash with water and air dry at RT and atmospheric pressure. This gave 45.8 g of the target compound (105% of theory).

LC-MS (Method 2): R _t = 0.98min

MS (ES +): m / z = 281 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.44 (s, 3H), 5.37 (s, 2H), 7.21 (quint., 2H), 7.52-7.61 (m, 1H), 8.01 (s, 1H), 8.06 (s, 1H).

Example 323A 3-[(2,6-difluorobenzyl) oxy] -5-methylpyridine-2-amine

Under argon, 91 g (324.7 mmol) of 3-[(2,6-difluorobenzyl) oxy] -5-methyl-2-nitropyridine from Example 322A was first placed in 980 ml of ethanol. 56.2 g (1.0 mol) of iron powder was added and the mixture was heated to reflux. 248 ml of a concentrated aqueous hydrochloric acid solution was slowly added dropwise, and the mixture was stirred under reflux for another 30 min. After cooling, about 2000 ml of water / ice (1/1) was added to the reaction mixture, and the mixture was stirred at RT for 30 min. The solution was concentrated until most of the solvent was removed. The aqueous phase was made alkaline with concentrated aqueous sodium hydroxide solution, 1200 ml of dichloromethane was added and the mixture was stirred vigorously for 1 h. The mixture was suction filtered through celite and repeatedly washed with a total of about 2800 ml of dichloromethane. The mother liquor was separated and the organic phase was dried and concentrated. This gave 77.8 g of the target compound (96% of theory).

LC-MS (Method 2): R _t = 0.57min

MS (ES +): m / z = 251 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.13 (s, 3H), 5.08 (s, 2H), 5.25 (s, 2H), 7.09 (d, 1H), 7.14-7.22 (m, 2H ), 7.37-7.41 (m, 1H), 7.49-7.57 (m, 1H).

Example 324A 8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 3.5 g (13.99 mmol) of 3-[(2,6-difluorobenzyl) oxy] -5-methylpyridine-2-amine from Example 323A and 9.6 ml (69.93 mmol) of Methyl 2-chloro-2-propanacetate was dissolved in 140 ml of ethanol, and the mixture was stirred at reflux with 500 mg of 3 Å molecular sieve overnight. 500 mg of 3 Å molecular sieve was added, and the mixture was stirred at reflux for another 16 hours. The reaction mixture was stirred at reflux for 8 days, and 3Å molecular sieves were added daily. The mixture was cooled and suction filtered, and the mother liquor was substantially concentrated. The obtained residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 9/1 to 7/3). This gave 3.8 g of the total compound (68% of theory, 1: 1 and 8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1 , 2-a] Mixture of methyl pyridine-3-carboxylate).

LC-MS (Method 2): R _t = 1.18min

MS (ES +): m / z = 361 (M + H) ⁺

Example 325A 8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridine-3-carboxylic acid

2.0 g (5.34 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridine-3- from Example 324A Ethyl carboxylate (1: 1 mixture of methyl ester and ethyl ester) was dissolved in 114 ml of THF / methanol (5/1), 5.34 ml (5.34 mmol) of a 1N aqueous sodium hydroxide solution was added and the mixture was stirred at RT overnight . The reaction mixture was stirred at 40 ° C for 4 days. After 3 days, 5.34 ml (5.34 mmol) of a 1N aqueous lithium hydroxide solution was added. After cooling, the mixture was acidified to pH 4 using 6N aqueous hydrochloric acid under ice cooling, and then the organic solvent was removed on a rotary evaporator. The precipitated solid was filtered by suction, washed with water and then dried under high vacuum. This gave 1.94 g of the target compound (99% of theory).

LC-MS (Method 2): R _t = 0.79min

MS (ES +): m / z = 347 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.19 (t, 3H), 2.36 (s, 3H), 2.95 (q, 2H), 5.31 (s, 2H), 7.08 (s, 1H), 7.26 (quin, 2H), 7.55-7.65 (m, 1H), 8.78 (s, 1H), 13.02-13.06 (m, 1H).

Example 326A Racemic-2-methylpentan-1,2-diamine dihydrochloride

Under ice-cooling, 1.0 g (8.91 mmol) of racemic-2-amino-2-methylpropionitrile was first put into 26.7 ml (26.74 mmol) of a 1 M solution of hydrochloric acid in ethanol, and 30 mg ( 0.13 mmol) of platinum (IV) oxide was hydrogenated at standard pressure overnight. Add another 30 mg (0.13 mmol) of platinum (IV) oxide and the reaction mixture was hydrogenated at 3 bar for 6 hours. The reaction mixture was filtered through celite, 9 ml (17.83 mmol) of a 2N solution of hydrochloric acid in ether was added to the filtrate, the mixture was concentrated and the product was dried under high vacuum. This gave 1.56 g of the target compound (92% of theory).

MS (ES +): m / z = 117 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.89 (t, 3H), 1.26-1.41 (m, 5H), 1.58-1.68 (m, 2H), 3.03-3.16 (m, 2H), 8.56 -8.74 (m, 4H).

Example 327A Racemic-2- (trifluoromethyl) piperidine-4-amine hydrochloride

115 mg (0.43 mmol) of racemic- [2- (trifluoromethyl) piperidin-4-yl] carbamic acid third butyl ester was first placed in 2.2 ml of ether, and 2.14 ml (4.28 mmol) of 2N hydrochloric acid in ether and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was dried under high vacuum. This gave 89 mg of the target compound (101% of theory).

Example 328A 8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid

8.0 g (24.66 mmol) of 8- (benzyloxy) -2,6-dimethyl from Example 238A Ethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester was dissolved in 526 ml of THF / methanol (5/1), 123 ml (123.31 mmol) of a 1N lithium hydroxide aqueous solution was added, and the mixture was stirred at 40 ° C. 6 hours. The reaction mixture was acidified to pH 5 with 6N aqueous hydrochloric acid under ice-cooling, and then the organic solvent was removed under reduced pressure. The precipitated solid was filtered by suction, washed with water and then dried under high vacuum. This gave 7.47 g of the target compound (96% of theory, 94% purity).

LC-MS (Method 2): R _t = 0.67min

MS (ES +): m / z = 297 (M + H) ⁺

Example 329A Racemic- [1-({[8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridin-3-yl] carbonyl} amino) -2-methyl Amyl-2-yl] carbamate

7.0 g (22.20 mmol, purity 94%) of 8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 328A, 10.13 g (26.65 mmol) of HATU and 11.6 ml (66.61 mmol) of N, N-diisopropylethylamine were first put into 141 ml of DMF, the mixture was stirred at room temperature for 20 min and 17.4 g (44.41 mmol, purity 74%) was added Racemic- (1-amino-2-methylpent-2-yl) carbamic acid third butyl ester from Example 390A. The mixture was stirred at RT for 1 hour, then 1.2 l of water was added and the mixture was stirred at RT for 1 hour. The formed solid was filtered off and dried under high vacuum. This gave 9.98 g of the target compound (88% of theory).

LC-MS (Method 2): R _t = 1.09min

MS (ES +): m / z = 495 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 1.18 (s, 3H), 1.21-1.33 (m, 2H), 1.38 (s, 9H), 1.46-1.59 (m , 1H), 1.65-1.76 (m, 1H), 2.28 (s, 3H), 2.55 (s, 3H), 3.41-3.54 (m, 2H), 5.27 (s, 2H), 6.50-6.60 (m, 1H ), 6.80-6.85 (m, 1H), 7.34-7.40 (m, 1H), 7.40-7.46 (m, 2H), 7.48-7.54 (m, 2H), 7.67 (t, 1H), 8.44 (s, 1H ).

Example 330A Racemic- (1-{[((8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino)}-2-methylpent-2- Butyl urethane

Under argon, 9.06 g (18.31 mmol) of the racemic- [1-({[8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] from Example 329A) Pyridine-3-yl] carbonyl} amino) -2-methylpent-2-yl] carbamic acid third butyl ester was first put into 189 ml of ethanol, and 1.95 g (1.83 mmol) of 10% carbon on palladium was added and The mixture was hydrogenated at standard pressure and RT for 90 min. The reaction mixture was filtered through celite, the filter cake was washed with ethanol and the filtrate was concentrated. This gave 7.2 g of the target compound (92% of theory).

LC-MS (Method 2): R _t = 0.86min

MS (ES +): m / z = 405 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 1.18 (s, 3H), 1.21-1.33 (m, 2H), 1.35-1.41 (s, 9H), 1.48-1.59 (m, 1H), 1.65-1.77 (m, 1H), 2.22 (s, 3H), 2.56 (s, 3H), 3.41-3.53 (m, 2H), 6.49 (d, 1H), 6.53-6.59 (m 1H), 7.63 (t, 1H), 8.34 (s, 1H).

Example 331A 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2- (trifluoromethyl) imidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 1.1 g (4.40 mmol) of 3-[(2,6-difluorobenzyl) oxy] -5-methylpyridine-2-amine from Example 323A and 4.8 g (21.98 mmol) of Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate was dissolved in 44 ml of ethanol and stirred with about 200 mg of 3Å molecular sieve under reflux overnight. Approximately 200 mg of 3 Å molecular sieves were added and the mixture was stirred for an additional 16 hours under reflux. The mixture was then stirred at reflux for 8 days, and 3Å molecular sieves were added daily. The mixture was cooled and suction filtered, the mother liquor was substantially completely concentrated and the resulting residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 9/1 to 7/3). This gave 600 mg of the target compound (33% of theory).

LC-MS (Method 2): R _t = 1.33min

MS (ES +): m / z = 415 (M + H) ⁺

Example 332A 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2- (trifluoromethyl) imidazo [1,2-a] pyridine-3-carboxylic acid

491 mg (1.19 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2- (trifluoromethyl) imidazo [1,2-a] pyridine from Example 331A Ethyl-3-carboxylic acid was dissolved in 26 ml of THF / methanol (5/1), 6 ml of a 1 N aqueous lithium hydroxide solution was added, and the mixture was stirred at RT for 2 hours. The reaction solution was adjusted to pH 6 using a 1N aqueous hydrochloric acid solution, and the organic solvent was distilled off. The formed precipitate was filtered off, washed with water and dried under high vacuum. This gave 336 mg of the target compound (73% of theory).

LC-MS (Method 2): R _t = 1.04min

MS (ES +): m / z = 387 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.42 (s, 3H), 5.35 (s, 2H), 7.20-7.30 (m, 3H), 7.56-7.66 (m, 1H), 8.84 (s , 1H).

Example 333A Enantiomer-{1-[({8-[(2,6-difluorobenzyl) oxy] -6-methyl-2- (trifluoromethyl) imidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate

50 mg (0.13 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2- (trifluoromethyl) imidazo [1,2-a] pyridine from Example 332A 3--3-carboxylic acid, 45.7 mg (0.14 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 0.07 ml (0.65 mmol) of 4-methyl Formaline was first placed in 0.43 ml of DMF, 35.6 mg (0.14 mmol) of the enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester from Example 289A was added and the mixture was placed in Stir at RT for 1 hour. A little water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 46 mg of the target compound (48% of theory).

LC-MS (Method 2): R _t = 1.40min

MS (ES +): m / z = 619 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.85 (t, 3H), 1.20 (s, 3H), 1.23-1.33 (m, 2H), 1.44-1.55 (m, 1H), 1.68-1.78 (m, 1H), 2.32 (s, 3H), 3.50-3.64 (m, 2H), 4.94-5.03 (m, 2H), 5.33 (s, 2H), 6.93-7.00 (m, 1H), 7.06 (s , 1H), 7.20-7.36 (m, 7H), 7.56-7.65 (m, 1H), 7.93 (s, 1H), 8.60-8.67 (m, 1H).

Example 334A (1-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino) ] Methyl} cyclohexyl) carbamate tert-butyl trifluoroacetate

100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy from Example 21A Methyl] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid, 145 mg (0.45 mmol) of (benzotriazol-1-yloxy) bisdimethylamino Methylium fluoroborate and 0.17 ml (1.51 mmol) of 4-methylmorpholine were first placed in 2 ml of DMF, and 82.5 mg (0.36 mmol) of [1- (aminomethyl) cyclohexyl] amine was added Tertiary butyl formate and stir the mixture at RT overnight. A little water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 163 mg of the target compound (82% of theory).

LC-MS (Method 2): R _t = 1.15min

MS (ES +): m / z = 543 (M-TFA + H) ⁺

Example 335A {3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] Cyclopentyl} third butyl carbamate (stereoisomer mixture)

100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 106 mg (0.33 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 0.17 ml (1.51 mmol) of 4-methylmorpholine were first placed in 1 ml of In DMF, 78.4 mg (0.33 mmol) of (3-aminocyclopentyl) carbamic acid tert-butyl ester hydrochloride was added and the mixture was stirred at RT overnight. Water was added to the reaction solution, and the formed solid was stirred at RT for 30 min, filtered, washed with water and dried under high vacuum. This gave 120 mg of the target compound (77% of theory).

LC-MS (Method 2): R _t = 0.94min

MS (ES +): m / z = 515 (M + H) ⁺

Example 336A Racemic-2-amino-3- (1,3-benzothiazol-2-yl) -2-methylpropionitrile

Put 3.0 g (14.12 mmol, purity 90%) of 1- (1,3-benzothiazol-2-yl) acetone into 28.2 ml (56.47 mmol) of a 2N ammonia methanol solution, and add 775 mg (15.81 mmol) Sodium cyanide and 1.8 g (15.81 mmol) of ammonium chloride and the mixture was stirred at reflux for 3 hours. The reaction solution was cooled and diluted with 90 ml of dichloromethane, the precipitated solid was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate 5/1 to 1/1). This gave 1.16 g of the target compound (29% of theory, 77% purity).

LC-MS (Method 2): R _t = 0.70min

MS (ES +): m / z = 218 (M + H) ⁺

Example 337A Racemic-3- (1,3-benzothiazol-2-yl) -2-methylpropan-1,2-diamine

100 mg (0.35 mmol, 77% purity) of racemic-2-amino-3- (1,3-benzothiazol-2-yl) -2-methylpropionitrile from Example 336A was first placed into 3.6 ml THF, and 0.23 ml (0.23 mmol) of a 1N lithium aluminum hydride in diethyl ether was added at 0 ° C under argon. The mixture was stirred at 0 ° C for 30 min and then at RT for 1 h. Carefully add 0.04 ml of water, 0.04 ml of a 2N aqueous sodium hydroxide solution, and 0.07 ml of water to the reaction mixture. The precipitate was filtered and washed with THF and a little methanol, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 10/1; dichloromethane / 2N ammonia methanol solution 20/1). This gave 17.6 mg of the target compound (21% of theory, 94% purity).

LC-MS (Method 15): R _t = 1.73min

MS (ES +): m / z = 222 (M + H) ⁺

Example 338A Racemic-5-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 94 mg (0.25 mmol) of HATU and 0.2 ml (1.13 mmol) of N, N-diisopropylethylamine were first put into 1.44 ml of DMF, and the mixture was stirred for 20 min, and then 64 mg (0.27 mmol) of external digestion was added. Spin-5-amino-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester and stir the mixture at RT overnight. Water was added to the reaction solution, and the precipitated solid was stirred at RT for 30 min, filtered, washed with water and dried under high vacuum. This gave 95 mg of the target compound (73% of theory).

LC-MS (Method 15): R _t = 1.07min

MS (ES +): m / z = 551 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.89-0.99 (m, 1H), 1.27-1.46 (m, 10H), 2.32 (s, 3H), 2.47 (s, 3H), 2.91-3.07 (m, 1H), 3.37-3.67 (m, 1H), 3.68-4.04 (m, 2H), 4.06-4.15 (m, 1H), 5.29 (s, 2H), 6.95 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.64 (m, 1H), 7.65-7.82 (m, 1H), 8.42-8.58 (m, 1H).

Example 339A 3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- 4- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate (mixture of stereoisomers)

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 94 mg (0.25 mmol) of HATU and 0.12 ml (0.68 mmol) of N, N-diisopropylethylamine were first put into 1.44 ml of DMF, the mixture was stirred for 20 min, and 69 mg (0.27 mmol) of racemic was added -3-Amino-4- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of stereoisomers) and the mixture was stirred at RT overnight. An additional 47 mg (0.13 mmol) of HATU and 0.05 ml (0.34 mmol) of N, N-diisopropylethylamine were added, and the mixture was stirred at RT for 15 min. Then 34 mg (0.13 mmol) of 3-amino-4- (trifluoromethyl) pyrrolidine-1-carboxylic acid third butyl ester (a mixture of stereoisomers) was added, and the mixture was heated to 60 ° C. Stir in oil bath overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 11 mg of the target compound (6% of theory, 80% purity).

LC-MS (Method 15): R _t = 1.12min

MS (ES +): m / z = 569 (M-TFA + H) ⁺

Example 340A Enantiomer- {2-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -2-methylbutyl} carbamic acid benzyl trifluoroacetate

282 mg (0.81 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylate from Example 265A Acid, 337 mg (0.89 mmol) of HATU and 0.4 ml (2.42 mmol) of N, N-diisopropylethylamine were first put into 5 ml of DMF, the mixture was stirred for 20 min, then 200 mg (0.85 mmol) was added 275A benzyl enantiomer- (2-amino-2-methylbutyl) carbamate and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 165 mg of the target compound (30% of theory).

LC-MS (Method 2): R _t = 1.07min

MS (ES +): m / z = 569 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 1.26 (s, 3H), 1.49-1.60 (m, 1H), 1.93-2.06 (m, 1H), 2.37 (s , 3H), 2.71 (s, 3H), 3.29-3.37 (m, 1H), 3.51-3.59 (m, 1H), 4.99 (s, 2H), 5.44 (s, 2H), 7.18-7.37 (m, 6H ), 7.50 (t, 1H), 7.65-7.75 (m, 2H), 8.41 (s, 1H).

Example 341A Racemic-3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] azacycloheptane-1-carboxylic acid tert-butyl trifluoroacetate

125 mg (0.38 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 157 mg (0.49 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 0.12 ml (1.13 mmol) of N-methylmorpholine were first placed in 2.4 ml In DMF, the mixture was stirred at RT for 10 min, then 105 mg (0.49 mmol) of racemic-3-aminoazepine-1-carboxylic acid third butyl ester was added and the mixture was stirred at RT overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 194 mg of the target compound (80% of theory).

LC-MS (Method 2): R _t = 1.11min

MS (ES +): m / z = 529 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.42 (s, 9H), 1.47-1.67 (m, 2H), 1.69-1.96 (m, 3H), 2.41 (br.s., 3H), 2.98-3.15 (m, 1H), 3.26-3.41 (m, 2H), 3.61-3.79 (m, 2H), 4.13-4.25 (m, 1H), 5.39 (s, 2H), 7.22-7.30 (m, 2H ), 7.33-7.51 (m, 1H), 7.57-7.67 (m, 1H), 8.06-8.26 (m, 1H), 8.42-8.61 (m, 1H).

Example 351A N- (third butoxycarbonyl) -3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine -3-yl} carbonyl) amino] -L-alanine methyl ester

300 mg (0.90 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 377 mg (1.17 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 0.5 ml (4.51 mmol) of N-methylmorpholine were first placed in 5.7 ml In DMF, the mixture was stirred at RT for 10 min, then 253 mg (0.99 mmol) of 3-amino-N- (third butoxycarbonyl) -L-alanine methyl ester hydrochloride was added and the mixture was stirred at RT Until overnight. About 40 ml of water was added to the reaction solution, and the mixture was stirred at RT for about 30 min. The solid was suction filtered, washed with water and dried under high vacuum. This gave 377 mg of the target compound (75% of theory).

LC-MS (Method 2): R _t = 0.96min

MS (ES +): m / z = 533 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (s, 9H), 2.31 (s, 3H), 2.47 (s, 3H), 3.55-3.69 (m, 5H), 4.28 (q, 1H ), 5.28 (s, 2H), 6.91-6.98 (m, 1H), 7.19-7.28 (m, 2H), 7.33 (d, 1H), 7.54-7.64 (m, 1H), 7.86 (t, 1H), 8.40-8.47 (m, 1H).

Example 352A Racemic-2-amino-2-methyl-3- [1- (5-methyl-1,2- Azol-3-yl) -1H-1,2,4-triazol-3-yl] propionitrile

860 mg (4.17 mmol) of 1- [1- (5-methyl-1,2- Azole-3-yl) -1H-1,2,4-triazol-3-yl] acetone was first placed in 8.3 ml of a 2N ammonia methanol solution, and 229 mg (4.67 mmol) of sodium cyanide and 556 mg (4.67 mmol) ) Ammonium chloride and the mixture was stirred at reflux for 4 hours. The reaction solution was cooled and diluted with 90 ml of dichloromethane, the obtained solid was filtered off, the filtrate was concentrated and the residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate: 4/1 to 1 / 1). This gave 761 mg of the target compound (78% of theory, 93% purity).

LC-MS (Method 15): R _t = 1.48min

MS (ES +): m / z = 233 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.51 (s, 3H), 2.82 (s, 2H), 3.08 (q, 2H), 3.33 (s, 3H), 6.81 (d, 1H), 9.25 (s, 1H).

Example 353A Racemic-2-methyl-3- [1- (5-methyl-1,2- Azol-3-yl) -1H-1,2,4-triazol-3-yl] propan-1,2-diamine

250 mg (1.00 mmol, purity 93%) of racemic-2-amino-2-methyl-3- [1- (5-methyl-1,2- Azol-3-yl) -1H-1,2,4-triazol-3-yl] propionitrile was first placed in 10.1 ml of THF, and 0.65 ml (0.65 mmol) of 1M was added under argon and 0 ° C. Lithium aluminum hydride in THF. The mixture was stirred at 0 ° C for 30 min and then at RT for 2 hours. At 0 ° C, 0.20 ml (0.20 mmol) of a 1 M solution of lithium aluminum hydride in THF was added dropwise and the mixture was then stirred at RT for 2 hours. At 0 ° C, another 0.40 ml (0.40 mmol) of a 1M lithium aluminum hydride in THF solution was added dropwise, and the mixture was stirred at RT for 2 hours. Carefully add 0.1 ml of water, 0.1 ml of a 2N aqueous sodium hydroxide solution, and 0.2 ml of water to the reaction mixture. The formed precipitate was filtered and washed with dichloromethane / methanol (10/1), and the filtrate was concentrated and dried under high vacuum. This gave 109 mg of the target compound (46% of theory).

LC-MS (Method 2): R _t = 0.17min

MS (ES +): m / z = 237 (M + H) ⁺

Example 354A Ethyl 2-chloro-3-cyclopropyl-3-oxopropanoate

13.5 ml (168.07 mmol) of dichlorothionine were first placed in 100 ml of dichloromethane. At 15 ° C, 25 g (160.07 mmol) of ethyl 3-cyclopropyl-3-pentoxypropionate were slowly added dropwise, and the mixture was stirred at RT for 2 hours. The reaction mixture was washed with 100 ml of water, a 5% strength sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution each time. The organic phase was dried over sodium sulfate, filtered and carefully concentrated on a rotary evaporator (bath temperature 25 ° C, 200 mbar). This gave 38 g of the target compound (109% of theory, purity of about 88%).

LC-MS (Method 2): R _t = 0.88min

MS (ES +): m / z = 191 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.92-1.03 (m, 2H), 1.03-1.14 (m, 2H), 1.22 (t, 3H), 2.22-2.30 (m, 1H), 4.19 -4.28 (m, 2H), 5.79 (s, 1H).

Example 355A 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 4.00 g (15.98 mmol) of 3-[(2,6-difluorobenzyl) oxy] -5-methylpyridine-2-amine from Example 323A and 17.31 g (79.92 mmol, purity 88%) of 2-chloro-3-cyclopropyl-3-oxopropanoic acid ethyl ester from Example 354A was dissolved in 160 ml of ethanol, and the mixture was stirred under reflux with about 2 g of 3 Å molecular sieve for 8 days (about 0.5 g was added daily) 3Å molecular sieve). The reaction mixture was cooled and suction filtered, and the mother liquor was concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate gradient: 95/5 to 7/3). This gave 0.6 g of the target compound (10% of theory).

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.93-1.01 (m, 4H), 1.36 (t, 3H), 2.08-2.17 (m, 1H), 2.35 (s, 3H), 4.38 (q 3H), 5.29 (s, 2H), 7.08 (s, 1H), 7.19-7.28 (m, 2H), 7.54-7.64 (m, 1H), 8.73 (s, 1H).

Example 356A 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6-methylimidazo [1,2-a] pyridine-3-carboxylic acid

100 mg (0.26 mmol) of 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6-methylimidazo [1,2-a] pyridine-3- from Example 355A Ethyl carboxylate was dissolved in 5.6 ml of THF / methanol (5/1), 1.3 ml (1.29 mmol) of a 1 N aqueous lithium hydroxide solution was added, and the mixture was stirred at RT for 2 days. The reaction solution was adjusted to pH 3 using a 1N aqueous hydrochloric acid solution, and the organic solvent was distilled off. The formed precipitate was filtered off, washed with water and dried under high vacuum. This gave 64 mg of the target compound (63% of theory, 91% purity).

LC-MS (Method 2): R _t = 0.92min

MS (ES +): m / z = 359 (M + H) ⁺

Example 357A Enantiomer- {1-[({2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl trifluoroacetate

50 mg (0.13 mmol, purity 91%) of 2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6-methylimidazo [1,2-a] from Example 356A Pyridine-3-carboxylic acid, 45 mg (0.14 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU) and 0.07 ml (0.64 mmol) of 4- Methylmorpholine was first placed in 0.5 ml of DMF, 35 mg (0.14 mmol) of the enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester from Example 289A was added and The mixture was stirred at RT until overnight. A little water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 75 mg of the target compound (82% of theory).

LC-MS (Method 2): R _t = 1.32min

MS (ES +): m / z = 591 (M-TFA + H) ⁺

Example 358A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methyl-6-[(trimethylsilyl) ethynyl] imidazo [1,2-a ] Pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester

514 mg (0.691 mmol) of the enantiomer- {1-[({6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate, 97 mg (0.138 mmol) of dichloro [bis (triphenylphosphine) Base)] Palladium and 26 mg (0.138 mmol) of copper (I) iodide Hexane and 7.5 ml of diisopropylethylamine. Then 407 mg (4.15 mmol) of ethynyl (trimethyl) silane was added dropwise and the mixture was stirred at 50 ° C. overnight. The reaction mixture was concentrated on a rotary evaporator. The residue was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 401 mg (90% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.53min

MS (ES +): m / z = 647 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.26 (s, 9H), 0.85 (t, 3H), 1.20 (s, 3H), 1.23-1.34 (m, 2H), 1.45-1.56 (m , 1H), 1.69-1.82 (m, 1H), 2.52 (s, 3H), 3.45-3.59 (m, 2H), 5.00 (s, 2H), 5.33 (s, 2H), 7.02-7.12 (m, 2H ), 7.20-7.37 (m, 7H), 7.53-7.66 (m, 1H), 7.84 (t, 1H), 8.78 (s, 1H).

Example 359A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6-ethynyl-2-methylimidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] benzyl carbamate

400 mg (0.62 mmol) of the enantiomer from Example 358A- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methyl-6-[(trimethylsilyl ) Ethynyl] imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester was first placed in 6.2 ml of methanol, and 256 mg (1.86 mmol) of potassium carbonate was added at RT and the mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated on a rotary evaporator. Ice-water was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 312 mg (89% of theory) of the title compound.

LC-MS (Method 2): R _t = 1.31min

MS (ES +): m / z = 575 (M + H) ⁺

360A Enantiomer-N- [2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl] acetamidamine (mirror isomer A)

5.80 g (20.19 mmol) of racemic-N- [2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl ] Acetylamine (described in: M.-C. Fernandez et al. Bioorg. Med. Chem. Lett. 2012, 22, 3056-3062) is separated by preparative separation on the palm phase into mirror isomers [tube Column: SFC Chiralpak AY-H, 20μm, 360 × 50mm, mobile phase: 85% Carbon dioxide, 15% isopropanol, flow rate: 400 ml / min; temperature: 38 ° C; back pressure: 80 bar; detection: 220 nm].

Mirror isomer A: Yield 2.20 g (> 99% ee)

R _t = 1.30min [Daicel Chiralpak AY-H, 5μm, 250 × 4.6mm; mobile phase: 70% carbon dioxide, 30% isopropanol; flow rate: 3ml / min; detection: 210nm].

Example 361A Enantiomer-2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-amine hydrochloride

Add 2.8 ml of a saturated solution of hydrogen chloride in methanol to 150 mg (0.52 mmol) of the enantiomer-N- [2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro from Example 360A -1,5-naphthyridin-4-yl] acetamidamine (mirror isomer A), and the mixture was stirred in a microwave at 80 ° C for 1 hour. The reaction mixture was concentrated, dissolved in acetonitrile / water (1: 1) and lyophilized. This gave 124 mg of the target compound (80% of theory).

LC-MS (Method 15): R _t = 2.05min

MS (ES +): m / z = 246 (M-HCl + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.96 (t, 3H), 1.47-1.69 (m, 3H), 2.29-2.39 (m, 1H), 3.41-3.52 (m, 1H), 4.50 -4.62 (m, 1H), 6.93 (br.s., 1H), 7.09 (d, 1H), 7.52 (d, 1H), 8.45 (br.s., 3H).

Example 362A Enantiomer-N- [2-methyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl] acetamidamine (mirror isomer A)

6.00 g (21.96 mmol) of racemic-N- [2-methyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl ] Acetylamine (described in: M.-C. Fernandez et al. Bioorg. Med. Chem. Lett. 2012, 22, 3056-3062) is separated by preparative separation on the palm phase into mirror isomers Column: SFC Chiralpak AY-H, 20 μm, 360 × 50 mm, mobile phase: 90% carbon dioxide, 10% methanol, flow rate: 400 ml / min; temperature: 38 ° C .; back pressure: 80 bar; detection: 220 nm].

Mirror isomer A: Yield: 2.41 g (> 99% ee)

R _t = 2.66min [Daicel Chiralpak AY-H, 5μm, 250 × 4.6mm; mobile phase: 90% carbon dioxide, 10% isopropanol; flow rate: 3ml / min; detection: 210nm].

Example 363A Enantiomer-2-methyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-amine hydrochloride

2.8 ml of a saturated solution of hydrogen chloride in methanol was added to 152 mg (0.56 mmol) of the enantio-N- [2-methyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro from Example 362A -1,5-naphthyridin-4-yl] acetamidin (mirror isomer A) (described in: M.-C. Fernandez et al. Bioorg. Med. Chem. Lett. 2012, 22, 3056-3062) , And the mixture was stirred in a microwave at 80 ° C for 1 hour. The reaction mixture was concentrated and lyophilized. This gave 147 mg of the target compound (97% of theory).

LC-MS (Method 2): R _t = 0.40min

MS (ES +): m / z = 232 (M-HCl + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.23 (d, 3H), 1.59 (q, 1H), 2.25-2.35 (m, 1H), 3.58-3.69 (m, 1H), 4.50-4.61 (m, 1H), 6.97-7.05 (m, 2H), 7.52 (d, 1H), 8.40 (br.s., 3H).

Example 364A 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2-propylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 3.0 g (11.99 mmol) of 3-[(2,6-difluorobenzyl) oxy] -5-methylpyridine-2-amine from Example 323A was first placed in 60 ml of ethanol. Then 18.48 g (95.90 mmol) of ethyl 2-chloro-3-p-oxohexanoate (described in: M. Altuna-Urquijo et al. Tetrahedron 2009, 65, 975-984) and 600 mg of 3 Å molecular sieve were added, and the mixture was refluxed Stir for 5 days. The reaction solution was concentrated and partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate = 95/5 to 8/2). Thus, 2.4 g of the target compound was obtained (47% of the theoretical value, and the purity was about 92%).

LC-MS (Method 2): R _t = 1.23min

MS (ES +): m / z = 389 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.90 (t, 3H), 1.35 (t, 3H), 1.60-1.70 (m, 2H), 2.37 (s, 3H), 2.87-2.94 (m , 2H), 4.35 (q, 2H), 5.31 (s, 2H), 7.10 (s, 1H), 7.21-7.29 (m, 2H), 7.55-7.65 (m, 1H), 8.74 (s, 1H).

Example 365A 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2-propylimidazo [1,2-a] pyridine-3-carboxylic acid

2.30 g (5.92 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2-propylimidazo [1,2-a] pyridine-3- from Example 364A Ethyl carboxylate was first put into 108 ml of THF, and 29 ml of water and 21.6 ml of methanol were added at RT. 1.24 g (29.61 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at RT for 16 hours. The reaction mixture was removed from the organic solvent and the resulting aqueous solution was solidified with semi-concentrated hydrochloric acid. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and concentrated. This gave 2.50 g of the target compound (115% of theory).

LC-MS (Method 2): R _t = 0.83min

MS (ES +): m / z = 361 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.89 (t, 3H), 1.61-1.72 (m, 2H), 2.41 (s, 3H), 2.95 (t, 2H), 5.35 (s, 2H ), 7.19-7.35 (m, 3H), 7.56-7.66 (m, 1H), 8.85 (s, 1H), 12.94-13.92 (br.s, 1H).

Example 366A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6-methyl-2-propylimidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester

100 mg (0.28 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6-methyl-2-propylimidazo [1,2-a] pyridine-3-carboxylate from Example 365A Acid, 127 mg (0.33 mmol) of HATU and 0.24 ml (1.39 mmol) of N, N-diisopropylethylamine were first placed in 2 ml of DMF, and the mixture was pre-stirred at RT for 10 min. Then 98.4 mg (0.42 mmol) of enantio- (1-amino-2-methylbut-2-yl) carbamic acid benzyl ester from Example 274A was added to the reaction solution, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, solvent: acetonitrile / water gradient with 0.05% formic acid). This gave 109 mg of the target compound (68% of theory).

LC-MS (Method 2): R _t = 1.15min

MS (ES +): m / z = 579 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.79-0.88 (m, 6H), 1.20 (s, 3H), 1.55-1.70 (m, 3H), 1.73-1.86 (m, 1H), 2.29 (s, 3H), 2.83 (t, 2H), 3.45-3.58 (m, 2H), 5.00 (s, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.03-7.10 (m, 1H ), 7.20-7.28 (m, 2H), 7.28-7.38 (m, 5H), 7.55-7.64 (m, 1H), 7.79 (t, 1H), 8.37 (s, 1H).

Example 367A Racemic- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amine] cyclobutyl} carbamic acid tert-butyl ester

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 206 mg (0.54 mmol) of HATU and 0.4 ml (2.26 mmol) of N, N-diisopropylethylamine were first placed in 4.4 ml of DMF, the mixture was stirred for 10 min, and then 101 mg (0.54 mmol) of Racemic- (2-aminocyclobutyl) carbamate tert-butyl ester and the mixture was stirred at RT overnight. Water was added to the reaction mixture, and the formed solid was stirred at RT for about 30 min and then filtered and washed thoroughly with water. This gave 185 mg of the target compound (82% of theory).

LC-MS (Method 2): R _t = 0.94min

MS (ES +): m / z = 501 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.37 (s, 9H), 1.48-1.67 (m, 2H), 1.87-2.02 (m, 2H), 2.30 (s, 3H), 2.45 (s , 3H), 3.99-4.12 (m, 1H), 4.23-4.35 (m, 1H), 5.28 (s, 2H), 6.90 (s, 1H), 7.20-7.29 (m, 3H), 7.54-7.64 (m , 1H), 8.17 (d, 1H), 8.35 (s, 1H).

Example 368A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] Cyclobutyl} Thirty Butyl Carbamate (Mirror Isomer A)

180 mg (0.37 mmol) of the racemic- {2-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2 -a] pyridin-3-yl} carbonyl) amino] cyclobutyl} carbamic acid third butyl ester is separated into the mirror isomers on the palm phase by preparative separation [column: SFC Chiralpak AZ-H, 5μm, 250 × 20mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 50ml / min; temperature: 20 ° C; detection: 220nm].

Mirror isomer A: Yield: 77 mg (> 99% ee)

R _t = 5.79min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate: 1ml / min; detection: 220nm].

Example 369A Enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] cyclobutyl} carbamic acid third butyl ester (mirror isomer B)

180 mg (0.37 mmol) of the racemic- {2-[({8-[(2,6- Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] cyclobutyl} carbamic acid third butyl ester Separated into mirror isomers on the opposite palm phase [column: SFC Chiralpak AZ-H, 5μm, 250 × 20mm, mobile phase: 50% isohexane, 50% ethanol, flow rate: 50ml / min; temperature: 20 ° C ; Detection: 220nm].

Mirror isomer B: Yield: 67 mg (> 99% ee)

R _t = 8.24min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate: 1ml / min; detection: 220nm].

Example 370A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridin-3-yl} Carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate

110 mg (0.32 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridine-3-carboxylate from Example 325A Acid, 133 mg (0.35 mmol) of HATU and 0.17 ml (0.95 mmol) of N, N-diisopropylethylamine were first put into 2 ml of DMF, and the mixture was stirred for 20 min, then 106 mg (0.36 mmol, purity 86%) of benzyl enantiomer- (1-amino-2-methylpent-2-yl) carbamate from Example 288A and the mixture was stirred at RT overnight. A little water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 181 mg of the target compound (82% of theory).

LC-MS (Method 2): R _t = 1.19min

MS (ES +): m / z = 579 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 1.17-1.24 (m, 6H), 1.25-1.35 (m, 2H), 1.44-1.57 (m, 1H), 1.69 -1.81 (m, 1H), 2.37 (s, 3H), 2.91 (q, 2H), 3.50-3.60 (m, 2H), 4.97-5.02 (m, 2H), 5.38 (s, 2H), 7.09 (s , 1H), 7.22-7.39 (m, 8H), 7.56-7.66 (m, 1H), 8.06-8.31 (m, 1H), 8.42 (s, 1H).

Example 371A Racemic-4-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] hexahydrocyclopenta [b] pyrrole-1 (2H) -carboxylic acid third butyl ester

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 94.4 mg (0.25 mmol) of HATU and 0.12 ml (0.68 mmol) of N, N-diisopropylethylamine were first put into 1.4 ml of DMF, the mixture was stirred for 20 min, and 61 mg (0.27 mmol) of externally added The cyclo-4-aminohexahydrocyclopenta [b] pyrrole-1 (2H) -carboxylic acid tert-butyl ester (commercially available; also described in WO 201056717 A1) and the mixture was stirred at RT overnight. Water was added to the reaction solution, and the precipitated solid was stirred at RT for 30 min, filtered, washed with water and dried under high vacuum. This gave 116 mg of the target compound (95% of theory).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 541 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.89-1.08 (m, 3H), 1.40 (s, 9H), 1.58-1.86 (m, 7H), 2.31 (s, 3H), 2.48 (s , 3H), 3.96-4.12 (m, 1H), 4.18-4.30 (m, 1H), 5.29 (s, 2H), 6.91 (s, 1H), 7.19-7.29 (m, 2H), 7.52-7.64 (m , 1H), 7.84-7.94 (m, 1H), 8.33 (s, 1H).

Example 372A Racemic-1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3-azabicyclo [3.2.0] heptane-3-carboxylic acid tert-butyl ester

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 94.4 mg (0.25 mmol) of HATU and 0.20 ml (1.13 mmol) of N, N-diisopropylethylamine were first put into 1.4 ml of DMF, the mixture was stirred for 20 min, and 57.5 mg (0.27 mmol) of Racemic-1-amino-3-azabicyclo [3.2.0] heptane-3-carboxylic acid tert-butyl ester (commercially available; CAS-No. 1251009-41-2) and the mixture Stir at RT until overnight. Water was added to the reaction solution, and the precipitated solid was stirred at RT for 30 min, filtered, washed with water and dried under high vacuum. This gave 97 mg of the target compound (80% of theory).

LC-MS (Method 2): R _t = 1.05min

MS (ES +): m / z = 527 (M + H) ⁺

Example 373A Racemic-3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -4-fluoropyrrolidine-1-carboxylic acid tert-butyl trifluoroacetate

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 112 mg (0.29 mmol) of HATU and 0.32 ml (1.81 mmol) of N, N-diisopropylethylamine were first put into 0.75 ml of DMF, the mixture was stirred for 10 min, and then 60 mg (0.29 mmol) of The cis-racemic-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester and the mixture was stirred at RT for 60 min. TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were combined, concentrated and lyophilized. This gave 98 mg of the target compound (68% of theory).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 519 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.41 (s, 3H), 2.53 (br.s., 3H), 3.27-3.37 (m, 1H), 3.55-3.62 (m, 4H), 4.59-4.77 (m, 1H), 5.17-5.35 (m, 1H), 5.39 (s, 2H), 7.21-7.30 (m, 2H), 7.32-7.49 (m, 1H), 7.57-7.67 (m, 1H ), 8.42-8.65 (m, 2H).

Example 374A 8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

710 mg (3.03 mmol) of 8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 239A, 730 mg (3.33 mmol) of 2- (bromomethyl) A solution of 43 ml of DMF of 1.1-fluoro-3-methoxybenzene and 2.17 g (6.67 mmol) of cesium carbonate was heated in an oil bath preheated to 60 ° C. for 30 min. The reaction mixture was poured into water and stirred for 60 min, and the precipitated solid was filtered by suction, washed with water and dried under high vacuum. This gave 859 mg of the target compound (72% of theory and purity of about 94%).

LC-MS (Method 2): R _t = 1.10min

MS (ES +): m / z = 373 (M + H) ⁺

Example 375A 8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid

859 mg (2.17 mmol, 94% purity) of 8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 374A Pyridine-3-carboxylic acid ethyl ester was dissolved in 46.8 ml of THF / methanol (5/1), 10.8 ml (10.8 mmol) of a 1N aqueous lithium hydroxide solution was added and the mixture was mixed. The mixture was stirred at RT until overnight. The reaction solution was solidified with a 1N aqueous hydrochloric acid solution, and the organic solvent was distilled off. The formed precipitate was filtered off, washed with water and dried under high vacuum. This gave 785 mg of the target compound (98% of theory, purity of about 94%).

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 345 (M + H) ⁺

Example 376A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methyl Pent-2-yl} carbamate benzyl trifluoroacetate

Add 54 mg (0.22 mmol) of enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester from Example 289A to 60 mg (0.20 mmol) of 8-[(2 from Example 28A , 6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid, 70 mg (0.22 mmol) of TBTU and 0.11 ml (0.99 mmol) of 4-methylmorpholine In 0.66 ml of DMF solution, the mixture was stirred at RT for 1 h. The reaction solution was diluted with water / TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and dried. This gave 117 mg of the target compound (91% of theory).

LC-MS (Method 2): R _t = 1.20min

MS (ES +): m / z = 537 (M + H) ⁺

Example 377A 8-[(2,6-difluoro-3-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

1.35 g (5.75 mmol) of 8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 239A and 4.12 g (12.66 mmol) of cesium carbonate were first charged. Place in 82ml of DMF. The mixture was heated to 60 ° C, then 1.50 g (6.33 mmol) of 2- (bromomethyl) -1,3-difluoro-4-methoxybenzene was added and the mixture was stirred at 60 ° C for 20 min. The reaction mixture was poured into about 500 ml of water and stirred for 30 min. The formed solid was filtered with suction, washed with water and dried under high vacuum. This gave 2.11 g of the title compound (86% of theory, 92% purity).

LC-MS (Method 2): R _t = 1.09min

MS (ES +): m / z = 391 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): 69 [ppm] = 1.35 (t, 3H), 2.37 (s, 3H), 3.87 (s, 3H), 4.29-4.38 (m, 2H), 5.30 ( s, 2H), 7.09 (s, 1H), 7.12-7.22 (m, 1H), 7.27-7.37 (m, 1H), 8.71 (s, 1H), [additional signal under solvent peak].

Example 378A 8-[(2,6-difluoro-3-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid

2.00 g (4.69 mmol) of 8-[(2,6-difluoro-3-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 377A Pyridine-3-carboxylic acid ethyl ester suspended in 50 ml of di To the alkane, 11.73 ml (23.46 mmol) of a 2N aqueous sodium hydroxide solution was added and the mixture was stirred at 90 ° C. for 5 h. The reaction solution was acidified with a 1 N aqueous hydrochloric acid solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated using a rotary evaporator. This gave 790 mg of the title compound. The aqueous phase was stirred again with ethyl acetate for 1.5 h, and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated using a rotary evaporator. This gave 70 mg of the title compound. The aqueous phase was stirred again with dichloromethane for 2 h and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 60 mg of the title compound. The aqueous phase was concentrated under reduced pressure and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 300 mg of the title compound as trifluoroacetate. This gave a total of 920 mg of the title compound (52% of theory) (some were trifluoroacetate).

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 363 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.36 (s, 3H), 3.87 (s, 3H), 5.29 (s, 2H), 7.06 (s, 1H), 7.12-7.23 ( m, 1H), 7.28-7.38 (m, 1H), 8.75 (s, 1H), 12.09-13.12 (br.s, 1H), [additional signal under solvent peak].

Example 379A 3-cyclopropyl-2,6-difluorobenzaldehyde

3.50 g (15.84 mmol) of 3-bromo-2,6-difluorobenzaldehyde was dissolved in 87.5 ml of toluene. An aqueous solution of 3.36 g (31.67 mmol) of sodium carbonate in 1.5 ml was added, and the mixture was stirred at RT for 10 min. Then 2.04 g (23.75 mmol) of cyclopropylboronic acid and 366 mg (0.32 mmol) of tris (triphenylphosphine) palladium (0) were added, and the mixture was stirred under reflux overnight. An additional 0.68 g (7.92 mmol) of cyclopropylboronic acid, 0.34 g (3.17 mmol) of sodium carbonate, and 183 mg (0.16 mmol) of tris (triphenylphosphine) palladium (0) were added and the mixture was stirred under reflux again. Until overnight. The reaction mixture was diluted and extracted with ethyl acetate. The aqueous phase was washed twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure at a bath temperature of 35 ° C. This gave 3.50 g of the title compound (92% of theory, 76% purity).

LC-MS (Method 13): R _t = 2.11min

MS (ES +): m / z = 183 (M + H) ⁺

Example 380A (3-cyclopropyl-2,6-difluorophenyl) methanol

Under argon and 0 ° C, 221 mg (5.84 mmol) of sodium borohydride was first placed into 47 ml of tetrahydrofuran. Add 189 ml of a tetrahydrofuran solution of 3.5 g (14.60 mmol) of 3-cyclopropyl-2,6-difluorobenzaldehyde from Example 379A. Then 14.8 ml of methanol was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 2 h. The reaction solution was added to about 88 ml of ice water and adjusted to about pH = 1 using a 2N sulfuric acid solution, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness on a rotary evaporator at a bath temperature of 30 ° C. The residue was treated with a little dichloromethane / methanol and purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate). Ester gradient = 10/1 to cyclohexane / ethyl acetate 5/1). The product fractions were combined and concentrated on a rotary evaporator at a bath temperature of 30 ° C. This gave 2.46 g of the title compound (86% of theory, 94% purity).

LC-MS (Method 13): R _t = 1.90min

MS (ES +): m / z = 167 (MH ₂ O + H) ⁺

Example 381A 8-[(3-Cyclopropyl-2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester trifluoroacetic acid salt

2.67 g (11.41 mmol) of 8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 239A was dissolved in 104 ml of THF. Add 2.46 g (12.55 mmol) of (3-cyclopropyl-2,6-difluorophenyl) methanol from Example 380A and 6.29 g (23.97 mmol) of triphenylphosphine. After adding 4.75 ml (23.97 mmol) of diisopropyl azodicarboxylate (DIAD), the reaction mixture was stirred at RT overnight. The mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate gradient = 10/1 to 5/1). The product fractions were concentrated and purified again by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 1.1 g of the title compound (19% of theory).

LC-MS (Method 2): R _t = 1.23min

MS (ES +): m / z = 401 (M-TFA + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.70-0.78 (m, 2H), 0.95-1.03 (m, 2H), 1.36 (t, 3H), 2.00-2.13 (m, 1H ), 2.40 (s, 3H), 4.33-4.40 (m, 2H), 5.32 (s, 2H), 7.08-7.28 (m, 3H), 8.75 (s, 1H), [additional signal under solvent peak] .

Example 382A 8-[(3-cyclopropyl-2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid trifluoroacetate

1.1 g (2.14 mmol) of 8-[(3-cyclopropyl-2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 381A Pyridine-3-carboxylic acid ethyl trifluoroacetate was suspended in 46 ml of di Alkane, 6.4 ml (12.8 mmol) of a 2N aqueous sodium hydroxide solution were added and the mixture was stirred at 90 ° C. overnight. The mixture was concentrated and TFA / water / acetonitrile was added to the residue. The formed solid was filtered off and washed with water. The product-containing filtrate was concentrated slightly and purified by preparative HPLC (RP18 column: mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). After combining with the filtered solid, the appropriate product-containing fractions are concentrated. This gave 950 mg of the title compound (91% of theory).

LC-MS (Method 2): R _t = 0.87min

MS (ES +): m / z = 373 (M-TFA + H) ⁺

Example 383A Enantiomer- {1-[({8-[(3-cyclopropyl-2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate

150 mg (0.31 mmol) of 8-[(3-cyclopropyl-2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine from Example 382A -3-carboxylic acid trifluoroacetate, 129 mg (0.34 mmol) of HATU and 0.22 ml (1.23 mmol) of N, N-diisopropylethylamine were first put into 2 ml of DMF, and the mixture was stirred for 20 min, then 89 mg (0.36 mmol) of benzyl enantiomer- (1-amino-2-methylpent-2-yl) carbamate (mirror isomer B) from Example 289A was added at RT and the mixture was stirred at RT for 4.5 h. A little water was added to the reaction solution, and the formed solid was filtered off. The solid was dissolved in TFA / water / acetonitrile and then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 159 mg of the title compound (69% of theory).

LC-MS (Method 2): R _t = 1.22min

MS (ES +): m / z = 605 (M-TFA + H) ⁺

The example shown in Table 15A is similar to Example 383A with the appropriate carboxylic acid and the appropriate amine [enantiomer- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester from Example 289A ( Enantiomer B); Enantiomer- (1-amino-2-methylbut-2-yl) carbamate from Example 274A (Enantiomer A); Enantiomer from Example 301A- (1-Amino-3-fluoro-2-methylprop-2-yl) benzyl carbamate (mirror isomer B)] was prepared using the reaction conditions described in the representative process 2.

Example 389A Racemic- (2-cyanopent-2-yl) carbamate tert-butyl ester

64.2 g (294.2 mmol) of di-tert-butyl dicarbonate were first placed in a reaction flask, and 30.0 g (267.4 mmol) of racemic-2-amino-2-methylvaleronitrile ( Described in: Deng, SL. Et al., Synthesis 2001, 2445-2449; Freifelder, M. et al., J. Am. Chem. Soc. 1960, 696-698. The mixture was stirred at RT overnight. Dichloromethane was then added and the mixture was washed twice with a 1 N aqueous sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered and concentrated at a bath temperature of 30 ° C. This gave 76.33 g (quantitative yield; third butanol can be detected in ¹ H-NMR) of the target compound.

LC-MS (Method 15): R _t = 2.39min

MS (ES +): m / z = 213 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.90 (t, 3H), 1.30-1.44 (m, 11H), 1.47 (s, 3H), 1.65-1.86 (m, 2H), 7.48 (br .s, 1H).

Example 390A Racemic- (1-amino-2-methylpent-2-yl) carbamic acid third butyl ester

13.50 g (47.13 mmol; some third butanol is present) of the racemic- (2-cyanopent-2-yl) carbamic acid third butyl ester from Example 389A was dissolved in 137 ml of a 7N ammonia methanol solution, and Under argon was added 14.6 g of Raney nickel (50% strength suspension solution). The reaction mixture was hydrogenated in an autoclave at 20-30 bar until overnight. The reaction mixture was filtered through celite, the filter cake was washed with methanol and the filtrate was concentrated. This gave 18.50 g of the title compound, which was used in the next step without further purification.

LC-MS (Method 15): R _t = 1.96min

MS (ES +): m / z = 217 (M + H) ⁺

Example 391A Racemic-3- (3,4-difluorophenoxy) -2-methylpropan-1,2-diamine

300 mg (1.41 mmol) of racemic-2-amino-3- (3,4-difluorophenoxy) -2-methylpropionitrile was first placed in 14.4 ml of anhydrous THF and placed under argon. At 0 ° C, 0.92 ml (0.92 mmol) of a 1 N lithium aluminum hydride in ether solution was added. The reaction solution was stirred at 0 ° C for 30 min and then slowly warmed to room temperature and stirred overnight. Carefully add 140 μl of water, 4140 μl of 2N aqueous sodium hydroxide solution, and 280 μl of water to the reaction mixture. The precipitate was filtered and filtered with Wash with THF and methanol, concentrate the filtrate and purify the residue by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 20/1). This gave 87 mg of the target compound (24% of theory; purity about 84%).

LC-MS (Method 15): R _t == 1.73min

MS (ES +): m / z = 217 (M + H) ⁺

Example 392A 8- (Benzyloxy) -2-methyl-6-vinylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

6.32 g (16.23 mmol) of 8- (benzyloxy) -6-bromo-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 237A, 6.52 g (48.69 mmol) ) Potassium vinyl trifluoroborate, 8.21 g (81.15 mmol) of triethylamine and 2.68 g (3.28 mmol) of 1,1'-bis (biphenylphosphino) ferrocene palladium (II) -di The methyl chloride complex was first put into 120 ml of 2-propanol and stirred at 90 ° C for 1 hour. Ethyl acetate and water were added to the reaction mixture, the mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic phase was washed twice with water and once with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered, concentrated and dried under high vacuum. The isolated crude product was directly reacted further without further purification.

LC-MS (Method 2): R _t = 1.17min

MS (ES +): m / z = 337 (M + H) ⁺

Example 393A 8- (Benzyloxy) -6-methylamido-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

The crude 8- (benzyloxy) -2-methyl-6-vinylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 392A was first placed in 200 ml of tetrahydrofuran / water ( 1: 1), and 10.42 g (1.64 mmol) of europium (VIII) oxide and 10.52 g (49.18 mmol) of sodium periodate were added. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate was then added, and the mixture was washed three times with water and once with a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (mobile phase: cyclohexane / ethyl acetate gradient; 80% cyclohexane to 10% cyclohexane). This gave 4.05 g of the title compound (74% of theory in two steps).

LC-MS (Method 2): R _t = 1.11min

MS (ES +): m / z = 339 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.39 (t, 3H), 2.63 (s, 3H), 4.37-4.44 (m, 2H), 5.38 (s, 2H), 7.28 ( d, 1H), 7.35-7.48 (m, 3H), 7.49-7.55 (m, 2H), 9.51 (s, 1H), 10.03 (s, 1H).

Example 394A 8- (Benzyloxy) -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

Under argon, 1.65 g (4.88 mmol) of 8- (benzyloxy) -6-methylamidino-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl from Example 393A The ester was suspended in 66 ml of absolute ethanol. 92 mg (2.44 mmol) of sodium borohydride was added to the reaction mixture, and the mixture was stirred at room temperature for 15 min. The reaction solution was removed from ethanol, and water was added to the residue. The aqueous phase was extracted three times with ethyl acetate. A saturated aqueous sodium chloride solution was added to the combined organic phases, the mixture was filtered through celite and the filter cake was washed with ethyl acetate. The two phases are separated from each other. The organic phase was dried over sodium sulfate, filtered, concentrated and dried under high vacuum. This gave 1.49 g of the title compound (90% of theory).

LC-MS (Method 2): R _t = 0.87min

MS (ES +): m / z = 341 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): 69 [ppm] = 1.36 (t, 3H), 4.32-4.39 (m, 2H), 4.55 (d, 2H), 5.29 (s, 2H), 5.45 ( t, 1H), 7.04 (s, 1H), 7.32-7.48 (m, 3H), 7.48-7.57 (m, 2H), 8.83-5.86 (m, 1H), [additional signal is hidden under the solvent peak].

Example 395A 8-Hydroxy-6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

1.31 g (3.85 mmol) of 8- (benzyloxy) -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 394A was placed in advance Into 99ml of ethanol. Under argon, 820 mg (0.77 mmol) of 10% activated carbon on palladium was added to the reaction solution, and the mixture was hydrogenated under standard pressure for 3 hours. The reaction mixture was filtered through a Millipore filter, the filter cake was washed with ethanol and the filtrate was concentrated. This gave 845 mg of the title compound (82% of theory, 94% purity).

LC-MS (Method 2): R _t = 0.51min

MS (ES +): m / z = 251 (M + H) ⁺

Example 396A 8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester

845 mg (3.38 mmol) of 8-hydroxy-6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid ethyl ester from Example 395A was dissolved in 48.4 ml of anhydrous DMF , 2.42 g (7.43 mmol) of cesium carbonate and 699 mg (3.38 mmol) of 2,6-difluorobenzyl bromide were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 500 ml of water and stirred at room temperature for 30 min. The formed solid was filtered off and washed with water. This gave 1.14 g of the title compound (87% of theory).

LC-MS (Method 2): R _t = 0.87min

MS (ES +): m / z = 377 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (t, 3H), 4.32-4.40 (m, 2H), 4.58 (d, 2H), 5.31 (s, 2H), 5.47 ( t, 1H), 7.14 (s, 1H), 7.18-7.31 (m, 2H), 7.45- 7.71 (m, 1H), 8.86-8.89 (m, 1H), [additional signals are hidden under the solvent peak].

Example 397A 8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid trifluoroacetate

1.08 g (2.78 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine from Example 396A Ethyl-3-carboxylate was suspended in 60.3 ml of di Alkane, and 8.35 ml (16.7 mmol) of a 2N aqueous sodium hydroxide solution were added. The reaction solution was stirred at 90 ° C. overnight. The reaction solution was acidified with a 1N aqueous hydrochloric acid solution, and then the solvent was evaporated. The residue was stirred with water and the solid was filtered off. The aqueous phase was concentrated and treated in acetonitrile / water / TFA. The formed product-containing solid was filtered. Thus, 1.19 g of the title compound was obtained. The filtrate was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave an additional 0.08 g of the title compound. A total of 1.27 g of the title compound was obtained (96% of theory).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 349 (M-TFA + H) ⁺

Example 398A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine-3 -Yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester

180 mg (0.38 mmol) of 8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridine- 3-carboxylic acid trifluoroacetate, 158 mg (0.42 mmol) of HATU and 0.26 ml (1.51 mmol) of N, N-diisopropylethylamine were first put into 3.2 ml of DMF, and the mixture was stirred for 20 min, then 109 mg (0.43 mmol) of enantio- (1-amino-2-methylpent-2-yl) carbamic acid benzyl ester (mirror isomer B) from Example 289A was added at room temperature and the mixture was at room temperature Stir for 1h. The reaction solution was washed with water, and the solid was stirred at room temperature for 30 min, filtered and washed with water. This gave 199 mg of the title compound (91% of theory).

LC-MS (Method 2): R _t = 0.99min

MS (ES +): m / z = 581 (M + H) ⁺

The examples shown in Table 16A are similar to Example 398A by 8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1, 2-a] pyridine-3-carboxylic acid trifluoroacetate is prepared by reacting the appropriate 274A and 301A amines described above under the conditions described:

Example 401A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (fluoromethyl) -2-methylimidazo [1,2-a] pyridine-3 -Yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl trifluoroacetate

198 mg (0.34 mmol) of the enantiomer from Example 398A- {1-[({8-[(2,6-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester was first placed in 3.4 ml of dichloromethane and added at -78 ° C 82.5 mg (0.51 mmol) of diethylaminosulfur trifluoride, and the mixture was stirred at -78 ° C for 90 min and then at room temperature for 30 min. During the -78 ° C reaction, an additional 27.5 mg (0.17 mmol) of diethylaminosulfur trifluoride was added. The reaction solution was then diluted with dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 191 mg of the title compound (70% of theory, 87% purity).

LC-MS (Method 2): R _t = 1.19min

MS (ES +): m / z = 583 (M-TFA + H) ⁺

The example shown in Table 17A is similar to Example 401A prepared by reacting the above alcohol with diethylaminosulfur trifluoride under the conditions described:

Example 404A Racemic-2-amino-5,5,5-trifluoro-2-methylvaleronitrile

8.0 g (57.1 mmol) of 5,5,5-trifluoropentan-2-one [CAS registration number: 1341078-97-4; commercially available, or this methyl ketone may be known and familiar from the literature Prepared by methods familiar to those skilled in the art, such as Example a) in two steps from 4,4,4-trifluorobutyraldehyde according to Y. Bai et al. Angewandte Chemie 2012, 51, 4112-4116; K. Hiroi et al. Synlett 2001, 263-265; K. Mikami et al. 1982 Chemistry Letters, 1349-1352; or b) from 4,4,4-trifluorobutyric acid according to AAWube et al. Bioorganic and Medical Chemistry 2011, 19, 567-579; GM Rubottom et al. Journal of Organic Chemistry 1983, 48, 1550-1552; T. Chen et al. Journal of Organic Chemistry 1996, 61, 4716-4719. The product can be separated by distillation or chromatography] First put into 47.8ml of 2N ammonia methanol solution, add 3.69g (75.4mmol) of sodium cyanide and 4.03g (75.4mmol) of ammonium chloride at room temperature and The mixture was stirred at reflux for 4 hours. The reaction mixture was cooled, diethyl ether was added and the resulting solid was filtered off. The solvent was removed from the filtrate by distillation at atmospheric pressure. This gave 8.7 g of the title compound (92% of theory) as a residue, which was used in the next step without further purification.

GC-MS (Method 14): R _t = 1.90min

MS (ES +): m / z = 151 (M-CH ₃ ) ⁺

Example 405A Racemic- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester

8.7 g (52.36 mmol) of racemic-2-amino-5,5,5-trifluoro-2-methylvaleronitrile from Example 404A was first put into 128 ml of tetrahydrofuran / water = 9/1, and Join 22.43 g (162.3 mmol) of potassium carbonate. At 0 ° C, 8.93 g (52.36 mmol) of benzyl chloroformate were slowly added dropwise. The mixture was then allowed to slowly warm to room temperature with stirring and stirred overnight at room temperature. The upper solvent was decanted and the residue was stirred twice with 100 ml of tetrahydrofuran each time, and the upper solvent was decanted each time. The combined organic phases were concentrated and the crude product was purified by silica gel chromatography (mobile phase: cyclohexane / ethyl acetate gradient 9/1 to 4/1). This gave 11.14 g of the title compound (68% of theory).

LC-MS (Method 2): R _t = 1.01min

MS (ES +): m / z = 301 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): 69 [ppm] = 1.58 (s, 3H), 2.08-2.21 (m, 2H), 2.24-2.52 (m, 2H), 5.09 (s, 2H), 7.29-7.41 (m, 5H), 8.17 (br.s, 1H).

Example 406A Enantio- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester (mirror isomer A)

11.14 g of racemic- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester from Example 405A was separated by preparative formula on the opposite palm phase to form a mirror image Structure [column: Daicel Chiralpak AZ-H, 5μm, SFC, 250 × 50mm, mobile phase: 94% carbon dioxide, 6% methanol, flow rate: 200ml / min, temperature: 38 ° C, pressure: 135 bar; detection: 210nm].

Mirror isomer A: 4.12g (about 79% ee)

R _t = 1.60min [SFC, Daicel Chiralpak AZ-H, 250 × 4.6mm, 5μm, mobile phase: 90% carbon dioxide, 10% methanol, flow rate: 3ml / min, temperature: 30 ° C, detection: 220nm].

LC-MS (Method 2): R _t = 1.01min

MS (ES +): m / z = 301 (M + H) ⁺

Example 407A Enantio- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester (mirror isomer B)

11.14 g of racemic- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester from Example 405A was separated by preparative formula on the opposite palm phase to form a mirror image Structure [column: Daicel Chiralpak AZ-H, 5μm, SFC, 250 × 50mm, mobile phase: 94% carbon dioxide, 6% methanol, flow rate: 200ml / min, temperature: 38 ° C, pressure: 135 bar; detection: 210nm].

Mirror isomer B: 4.54g (about 70% ee; purity about 89%)

R _t = 1.91min [SFC, Daicel Chiralpak AZ-H, 250 × 4.6mm, 5μm, mobile phase: 90% carbon dioxide, 10% methanol, flow rate: 3ml / min, temperature: 30 ° C, detection: 220nm].

LC-MS (Method 2): R _t = 1.01min

MS (ES +): m / z = 301 (M + H) ⁺

Example 408A Enantio- (1-amino-5,5,5-trifluoro-2-methylpent-2-yl) carbamic acid benzyl ester (mirror isomer A)

4.12 g (13.17 mmol) of the enantiomer- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester (Mirror Isomer A) from Example 406A was dissolved in 39 ml In a 7N ammonia methanol solution, and 4 g of Raney nickel (50% strength suspension solution) were added under argon. The reaction mixture was hydrogenated in an autoclave at 20-30 bar until overnight. An additional 1 g of Raney nickel (50% strength suspension solution) was added and the reaction mixture was hydrogenated in an autoclave at 20-30 bar for 5 h. The reaction mixture was filtered through celite, the filter cake was rinsed with methanol and the filtrate was concentrated. This gives 3.35g (56% of the theoretical value; (67% purity) of the title compound, which was used in the next step without further purification.

LC-MS (Method 7): R _t = 1.68min

MS (ES +): m / z = 305 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.13 (s, 3H), 1.40 (br.s, 2H), 1.70-1.80 (m, 1H), 1.83-1.95 (m, 1H ), 2.08-2.2 (m, 2H), 4.98 (s, 2H), 6.85 (br.s, 1H), 7.28-7.41 (m, 5H).

Example 409A Enantio- (1-amino-5,5,5-trifluoro-2-methylpent-2-yl) carbamic acid benzyl ester (mirror isomer B)

4.54 g (13.45 mmol; purity about 89%) of the enantio- (2-cyano-5,5,5-trifluoropent-2-yl) carbamic acid benzyl ester (image isomer B from Example 407A) ) Was dissolved in 39 ml of a 7N ammonia methanol solution, and 5 g of Raney nickel (a 50% strength suspension solution) was added under argon. The reaction mixture was hydrogenated in an autoclave at 20-30 bar for 3 h. The reaction mixture was filtered through celite, the filter cake was washed with methanol and the filtrate was concentrated. This gave 4.20 g (97% of theory; purity about 95%) of the target compound, which was used in the next step without further purification.

LC-MS (Method 15): R _t = 2.19min

MS (ES +): m / z = 305 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.13 (s, 3H), 1.40 (br.s, 2H), 1.69-1.80 (m, 1H), 1.83-1.96 (m, 1H ), 2.07-2.22 (m, 2H), 4.98 (s, 2H), 6.85 (br.s, 1H), 7.27-7.40 (m, 5H).

Example 410A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer A)

500 mg (1.51 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 629 mg (1.66 mmol) of HATU and 583 mg (4.51 mmol) of N, N-diisopropylethylamine were first put into 9.6 ml of DMF, and the mixture was stirred at RT for 20 min. Then 957 mg (2.11 mmol; purity about 67%) of enantio- (1-amino-5,5,5-trifluoro-2-methylpent-2-yl) carbamic acid benzyl ester from Example 408A ( Isomer A) and the mixture was stirred at RT overnight. Approximately 70 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 45 min. The resulting solid was filtered off, washed thoroughly with water and dried under high vacuum. This gave 969 mg (99% of theory) of the title compound, which was used in the next step without further purification.

LC-MS (Method 2): R _t = 1.11min

MS (ES +): m / z = 619 (M + H) ⁺

Example 411A Enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer B)

500 mg (1.51 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 629 mg (1.66 mmol) of HATU and 583 mg (4.51 mmol) of N, N-diisopropylethylamine were first put into 9.6 ml of DMF, and the mixture was stirred at RT for 20 min. Then 675 mg (2.11 mmol; purity about 95%) of the enantio- (1-amino-5,5,5-trifluoro-2-methylpent-2-yl) carbamic acid benzyl ester from Example 409A ( Isomer B) and the mixture was stirred at RT overnight. Approximately 70 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 45 min. The resulting solid was filtered off, washed thoroughly with water and dried under high vacuum. This gave 917 mg (98% of theory) of the title compound, which was used in the next step without further purification.

LC-MS (Method 2): R _t = 1.14min

MS (ES +): m / z = 619 (M + H) ⁺

Example 412A Enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} (Carbonyl) amino] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer A)

300 mg (0.86 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylate from Example 265A Acid, 358 mg (0.94 mmol) of HATU and 332 mg (2.57 mmol) of N, N-diisopropylethylamine were first placed in 5.5 ml of DMF, and the mixture was stirred at RT for 20 min. Then 545 mg (1.20 mmol; purity about 67%) of enantio- (1-amino-5,5,5-trifluoro-2-methylpent-2-yl) carbamic acid benzyl ester from Example 408A ( Isomer A) and the mixture was stirred at RT for 2 h. About 50 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 45 min. The resulting solid was filtered off, washed thoroughly with water and dried under high vacuum. This gave 553 mg (88% of theory; 87% purity) of the title compound, which was used in the next step without further purification.

LC-MS (Method 2): R _t = 1.13min

MS (ES +): m / z = 637 (M + H) ⁺

Example 413A Enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} (Carbonyl) amino] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer B)

300 mg (0.86 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylate from Example 265A The acid, 358 mg (0.94 mmol) of HATU and 332 mg (2.57 mmol) of N, N-diisopropylethylamine were first placed in 5.5 ml of DMF, and the mixture was stirred at RT for 20 min. Then 384 mg (1.20 mmol; purity about 95%) of the enantio- (1-amino-5,5,5-trifluoro-2-methylpent-2-yl) carbamic acid benzyl ester from Example 409A ( Image isomer B), and the mixture was stirred at RT for 2 h. About 50 ml of water was added to the reaction solution, and the mixture was stirred at room temperature for 45 min. The resulting solid was filtered off, washed thoroughly with water and dried under high vacuum. This gave 540 mg (96% of theory) of the title compound, which was used in the next step without further purification.

LC-MS (Method 2): R _t = 1.16min

MS (ES +): m / z = 637 (M + H) ⁺

Example 414A Racemic- {2- (3-acetamidophenyl) -2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridin-3-yl} carbonyl) amino] ethyl} carbamic acid third butyl ester trifluoroacetate

50 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 63 mg (0.17 mmol) of HATU and 58 mg (0.45 mmol) of N, N-diisopropylethylamine were first placed in 0.5 ml of DMF, and the mixture was stirred at RT for 10 min. Then 51 mg (0.17 mmol) of [2- (3-acetamidophenyl) -2-aminoethyl] carbamic acid third butyl ester was added, and the mixture was stirred at RT for 2h. Acetonitrile, TFA, and water were added to the reaction mixture, and the product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 100 mg (92% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.91min

MS (ES +): m / z = 608 (M-TFA + H) ⁺

The example shown in Table 18A is similar to Example 414A by 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine from Example 21A A 3-carboxylic acid is prepared by reacting with an appropriate amine and HATU under the reaction conditions described in Representative Process 2.

Example 417A Racemic-3-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] methyl} timorpholine-4-carboxylic acid tert-butyl ester

320 mg (0.717 mmol) of racemic-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- (timorpholin-3-yl) from Example 366 (Methyl) imidazo [1,2-a] pyridine-3-carboxamide, 217 mg (2.150 mmol) of triethylamine and 156 mg (0.717 mmol) of di-tert-butyl dicarbonate were first placed in 3.0 ml of In methyl chloride, and the mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with dichloromethane, washed twice with water, dried over sodium sulfate, concentrated on a rotary evaporator and dried under high vacuum. The title compound (292 mg, 75% of theory) was used in the next step without further purification.

LC-MS (Method 16): R _t = 1.26min

MS (ESI +): m / z = 547 (M + H) ⁺

Example 418A Racemic-3-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] methyl} timorpholine-4-carboxylic acid tert-butyl 1,1-dioxide trifluoroacetate

At 0 ° C, 118 mg (0.686 mmol) of 3-chloroperoxybenzoic acid was added to 150 mg (0.274 mmol) of the racemic 3-{[({8-[(2,6-difluorobenzyl) ) Oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] methyl} thiamorpholine-4-carboxylic acid tert-butyl ester In 3.3 ml of a dichloromethane solution, the mixture was stirred at 0 ° C for 70 min. The reaction mixture was diluted with dichloromethane, washed three times with a 1N sodium hydroxide aqueous solution and once with a 10% strength sodium chloride aqueous solution, dried over sodium sulfate, and concentrated using a rotary evaporator. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 59 mg of the target compound (31% of theory).

LC-MS (Method 16): R _t = 1.10min

MS (ESI +): m / z = 579 (M-TFA + H) ⁺

Example 419A Racemic- (2-amino-2-cyanoethyl) carbamate benzyl trifluoroacetate

500 mg (3.16 mmol) of racemic-2,3-diaminopropionitrile dihydrochloride was first placed in 1.7 ml of anhydrous dichloromethane. At room temperature, 3.27 g (25.31 mmol) of N, N-diisopropylethylamine and 586.2 mg (3.16 mmol) of benzyl chloroformate were added, and the mixture was stirred at room temperature overnight. TFA and water were added to the reaction solution, and the product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). This gave 125 mg of the title compound (12% of theory).

LC-MS (Method 13): R _t = 1.31min

MS (ES +): m / z = 220 (M-TFA + H) ⁺

Example 420A Racemic- {2-cyano-2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] ethyl} carbamate benzyl trifluoroacetate

113 mg (0.34 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was first Put in 0.55 ml of anhydrous DMF, add 136 mg (0.36 mmol) of HATU and 132 mg (1.02 mmol) of N, N-diisopropylethylamine, stir the mixture at room temperature for 20 min and then heat to 60 ° C . 125 mg (0.38 mmol) of the racemic- (2-amino-2-cyanoethyl) carbamic acid benzyl ester trifluoroacetate from Example 419A was dissolved in 0.28 ml of anhydrous DMF, and 44 mg (0.34 mmol) ) N, N-diisopropylethylamine was added dropwise to the reaction solution heated to 60 ° C, and the mixture was stirred at 60 ° C for 1 h. . Water / TFA / acetonitrile was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: Acetonitrile / water gradient (0.1% TFA). This gave 151 mg of the title compound (68% of theory).

LC-MS (Method 2): R _t = 0.99min

MS (ES +): m / z = 534 (M-TFA + H) ⁺

Operation example Example 1 N- (9-cyclopropyl-9-azabicyclo [3.3.1] non-3-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide

70 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (0.22 mmol) and 209 mg of O- (7 -Azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU, 0.55 mmol) and 85 mg of N, N-diisopropylethylamine (0.66 mmol) were first put into 1.5 ml of DMF and stirred for 15 min. 59 mg of 9-cyclopropyl-9-azabicyclo [3.3.1] non-3-amine (0.33 mmol) was added, and the mixture was stirred at RT overnight. The mixture was then stirred again at 60 ° C overnight. 12 ml of water was added to the reaction solution, and the formed precipitate was filtered off, washed with water and dried. The resulting residue was purified by silica gel chromatography (mobile phase: dichloromethane / methanol 40: 1). This gave 60 mg of the title compound (53% of theory, 94% purity).

LC-MS (Method 2): R _t = 0.63min

MS (ES +): m / z = 481 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.24 (br s, 2H), 0.45 (d, 2H), 1.04 (d, 2H), 1.48-1.56 (m, 3H), 1.86-1.1.97 (m, 2H), 2.00-2.12 (m, 1H), 2.15-2.28 (m, 2H), 2.30-2.38 (m, 1H), 2.49 (s, 3H), 3.19 (d, 2H), 4.09-4.23 (m, 1H), 5.30 (s, 2H), 6.90 (t, 1H), 6.99 (d, 1H), 7.23 (t, 2H), 7.54-7.68 (m, 2H), 8.50 (d, 1H).

Example 2 Racemic-N- (1-amino-4,4,4-trifluorobut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide

555 mg of racemic-N- (1-azido-4,4,4-trifluorobut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2- Methylimidazo [1,2-a] pyridine-3-carboxamide (Example 41A, 1.19 mmol) was first placed in 74 ml of ethanol, 126 mg of activated carbon was added to palladium (10%), and the mixture was subjected to standard hydrogen Hydrogenation at atmospheric pressure and RT for 60 min. The reaction solution was filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fraction was treated in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 473 mg of the title compound (88% of theory).

LC-MS (Method 2): R _t = 0.65min

MS (ES +): m / z = 443 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.92 (br s, 2H), 2.48-2.60 (m, 3 + 1H), 2.62-2.80 (m, 3H), 4.18-4.30 (m, 1H) , 5.30 (s, 2H), 6.93 (t, 1H), 7.00 (d, 1H), 7.22 (t, 2H), 7.59 (quint, 1H), 7.79 (br s, 1H), 8.53 (d, 1H) .

Example 3 Enantiomer-N- (1-amino-4,4,4-trifluorobut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

Example 2 was separated into the mirror isomers by preparative separation on the opposite palm phase. [Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm; Mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine; flow rate 15ml / min; 45 ° C; detection: 220nm]

Mirror isomer B: Yield: 154 mg (99% purity,> 99% ee)

R _t = 16.57min [Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm] .

The examples shown in Table 1 were prepared similarly to Example 2.

a) Subsequent processing of the anhydrous phase after preparative HPLC.

Example 6 Enantiomer-N- (1-amino-6,6,6-trifluorohex-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

Example 4 (388 mg) was separated into mirror isomers by preparative separation on the opposite palm phase. [Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm; Mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine; flow rate 15ml / min; 45 ° C; detection: 220nm]

Mirror isomer B: Yield: 136 mg (99% purity,> 99% ee)

R _t = 17.00min [Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm] .

Example 7 Enantiomer-N- [1-amino-5,5,5-trifluoro-4- (trifluoromethyl) pent-2-yl] -8-[(2,6-difluorobenzyl) oxy ] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

Example 5 (140 mg) was separated into a mirror image by preparative separation on the opposite palm phase 体 物。 Structure. [Column: Daicel Chiralpak OD-H, 5μm, 250 x 20mm; Mobile phase: 70% different Hexane, 30% ethanol + 0.2% diethylamine; flow rate 20ml / min; 25 ° C; detection: 230nm]

Mirror isomer A: Yield: 31 mg (> 99% ee)

R _t = 4.47min [Daicel Chiralpak OD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; detection: 250nm].

Example 8 N-[(2R) -1-aminohex-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine- 3-carboxamide

42 mg of N-[(2R) -1-azidohex-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2- a) Pyridine-3-carboxamide (Example 44A, 0.095 mmol) was first placed in 0.78 ml To THF / water (10: 1.5), 28.3 mg of triphenylphosphine (0.108 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was purified by preparative thick layer chromatography (mobile phase ethyl acetate: dichloromethane: diethylamine = 2: 1: 0.1). The combined product fractions were purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fraction was treated in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 17 mg of the title compound (41% of theory).

LC-MS (Method 1): R _t = 0.88min

MS (ES +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88 (t, 3H), 1.21-1.39 (m, 4H), 1.42-1.67 (m, 2H), 2.73 (d, 2H), 3.92-4.08 ( m, 1H), 5.30 (s, 2H), 6.93 (t, 1H), 7.00 (d, 1H), 7.22 (t, 2H), 7.56-7.7.62 (m, 2H), 8.56 (d, 1H) .

Example 9 Racemic-N- [2-amino-1- (4-fluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide

7 ml of a 2M solution of hydrochloric acid in ether (14 mmol) was added to 363 mg of {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a ] Pyridin-3-yl} -carbonyl) amino] -2- (4-fluorophenyl) ethyl} carbamate in third butyl ester (Example 79A, 0.63 mmol), and the mixture was stirred at RT for 3 h. The resulting precipitate was filtered, washed with ether, and dissolved in dichloromethane and methanol. And washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered and the filtrate was concentrated and dried under high vacuum. This gave 275 mg of the title compound (96% of theory).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 455 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.62 (br s, 2H), 2.60 (s, 3H), 2.85-2.96 (m, 2H), 4.98 (t, 1H), 5.31 (s, 2H ), 6.90 (t, 1H), 6.99 (d, 1H), 7.18 (t, 2H), 7.22 (t, 2H), 7.41 (dd, 2H), 7.59 (quint, 1H), 8.20 (br s, 1H ), 8.53 (d, 1H).

Example 10 Enantio-N- [2-amino-1- (4-fluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

Example 9 (242 mg) was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 100% ethanol + 0.2% diethylamine , Flow rate 15ml / min; 45 ° C, detection: 220nm].

Mirror isomer B: Yield: 110 mg (99% purity, about 99% ee)

R _t = 10.25min [Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 45 ° C; detection: 235nm] .

Example 11 Racemic-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamide

3.1 ml of a 2M solution of hydrochloric acid in ether (6.2 mmol) was added to 355 mg of racemic- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo) [1,2-a] pyridin-3-yl} carbonyl) amino] -2- (3,4-difluorophenyl) ethyl} carbamic acid third butyl ester (Example 77A, 0.62 mmol), and The mixture was stirred at RT for 5.5 h. The resulting precipitate was filtered, washed with diethyl ether, suspended in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered and the filtrate was concentrated and dried under high vacuum. This gave 279 mg of the title compound (94% of theory).

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 473 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.18 (br s, 2H), 2.60 (s, 3H), 2.87-2.97 (m, 2H), 4.99 (t, 1H), 5.31 (s, 2H ), 6.91 (t, 1H), 7.01 (d, 1H), 7.19-7.28 (m, 3H), 7.36-7.51 (m, 2H), 7.59 (quint, 1H), 8.21 (br s, 1H), 8.54 (d, 1H).

Example 12 (Mirror image isomer A) Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

Example 11 (250 mg) was separated into mirror isomers by preparative separation on a counter palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, flow rate 15ml / min; 45 ° C, detection: 220nm]. The product fractions were concentrated, treated in water / acetonitrile and freeze-dried. The product was then purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The combined fractions were lyophilized and the residue was dissolved in ethyl acetate and washed with a little saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated and dried under high vacuum.

Mirror isomer A: Yield: 88mg (99% purity, about 94% ee)

R _t = 7.55min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 45 ° C; detection: 235nm] .

LC-MS (Method 2): R _t = 0.78min

MS (ES +): m / z = 473 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.59 (s, 3H), 2.88-3.01 (m, 2H), 5.02 (t, 1H), 5.31 (s, 2H), 6.91 (t, 1H) , 7.01 (d, 1H), 7.19-7.29 (m, 3H), 7.36-7.52 (m, 2H), 7.59 (quint, 1H), 8.21 (br s, 1H), 8.54 (d, 1H).

Specific optical rotation [α] (436nm, 20.4 ℃) = + 23.8 ° (c = 0.0053g / ml, acetonitrile)

Example 13 (Mirror image isomer B) Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

19 ml of a 2M solution of hydrochloric acid in ether (38 mmol) was added to 2.18 g of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridin-3-yl} carbonyl) amino] -2- (3,4-difluorophenyl) ethyl} carbamic acid third butyl ester (Example 118A, 3.80 mmol), and the mixture Stir at RT until overnight. The reaction mixture was diluted with diethyl ether. The precipitate was filtered and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered and the filtrate was concentrated and lyophilized. This gave 1.85 g of the title compound (quantitative).

LC-MS (Method 2): R _t = 0.80min

MS (ES +): m / z = 473 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.55 (br s, 2H), 2.59 (s, 3H), 2.85-2.95 (m, 2H), 4.97 (t, 1H), 5.31 (s, 2H ), 6.91 (t, 1H), 7.01 (d, 1H), 7.19-7.28 (m, 3H), 7.36-7.51 (m, 2H), 7.59 (quint, 1H), 8.21 (br s, 1H), 8.54 (d, 1H).

Specific rotation [α] (436nm, 19.9 ℃) =-23.5 ° (c = 0.00505g / ml, acetonitrile)

Example 14 Racemic-N- [2-amino-1- (4-chlorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide dihydrochloride

Add 3.5 ml (7.0 mmol) of a 2 M solution of hydrochloric acid in ether to 396 mg of racemic- {2- (4-chlorophenyl) -2-[({8-[(2,6-difluorobenzyl) Oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] ethyl} carbamic acid third butyl ester (Example 78A, 0.69 mmol), and the mixture was Stir at RT for 5.5 h. The resulting precipitate was filtered, washed with ether and dried under high vacuum. This gave 341 mg of the title compound (90% of theory).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 471 (M-2HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.69 (s, 3H), 3.16-3.28 (m, 1H), 3.38-3.53 (m, 1H), 5.40-5.49 (m, 3H), 7.23 ( t, 2H), 7.34 (br s, 1H), 7.41-7.67 (m, 6H), 8.20-8.43 (m, 3H), 8.65 (d, 1H), 9.39 (br s, 1H).

Example 15 Enantio-N- [2-amino-1- (4-chlorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

288 mg of the Example 14 compound was suspended in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated and dried under high vacuum. The crude product (279 mg) was separated into mirror isomers on the palm phase by preparative separation [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 30% isohexane, 70% ethanol + 0.2% diethylamine, flow rate 15ml / min; 45 ° C, detection: 220nm]. The product was repurified with silica gel (mobile phase: from dichloromethane to dichloromethane: methanol = 10: 1). It was then further purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% TFA). The product fraction was dissolved in ethyl acetate and washed twice with a little saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered and the filtrate was concentrated and dried under high vacuum overnight.

Mirror isomer B: Yield: 62 mg (99% purity, 99% ee)

R _t = 8.77min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 60% isohexane, 40% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 35 ° C; detection: 235nm] .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.04 (br s, 2H), 2.60 (s, 3H), 2.85-2.95 (m, 2H), 4.98 (t, 1H), 5.30 (s, 2H ), 6.90 (t, 1H), 7.02 (d, 1H), 7.22 (t, 2H), 7.38-7.44 (m, 4H), 7.59 (quint, 1H), 8.20 (br s, 1H), 8.53 (d , 1H).

Example 16 Racemic-N- (2-amino-1-phenylethyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] - Pyridine-3-carboxamide dihydrochloride

15.75 ml of a 2M solution of hydrochloric acid in ether (31.5 mmol) was added to 370 mg of racemic- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo) [1,2-a] pyridin-3-yl} carbonyl) amino] -2-phenylethyl} carbamate in third butyl ester (Example 80A, 0.69 mmol), and the mixture was stirred at RT for 3.5 h. The resulting precipitate was filtered, washed with ether and dried under high vacuum. This gave 306 mg of the title compound (85% of theory, 98% purity).

LC-MS (Method 2): R _t = 0.70min

MS (ES +): m / z = 437 (M-2HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.65 (s, 3H), 3.19-3.29 (m, 1H), 3.35-3.54 (m, 1H), 5.38-5.49 (m, 3H), 7.21- 7.54 (m, 10H), 7.60 (quint, 1H), 8.12-8.32 (m, 2H), 8.66 (d, 1H), 9.09 (br s, 1H).

The examples shown in Table 2 were prepared similarly to Example 16.

Example 18 Enantio-N- (2-amino-1-phenylethyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine -3-carboxamide (mirror isomer B)

276 mg of the compound of Example 16 was suspended in ethyl acetate / dichloromethane (1: 1) and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product (247 mg) was separated into mirror isomers on the opposite palm phase by preparative separation [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 30% isohexane, 70% ethanol + 0.2% diethylamine, flow rate 15ml / min; 45 ° C, detection: 220nm]. The resulting product was repurified on silica gel (mobile phase: from dichloromethane to dichloromethane: methanol = 10: 1). It was then further purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% TFA). The product fractions were concentrated, dissolved in ethyl acetate and washed with a little saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated.

Mirror isomer B: Yield: 78 mg (98% ee)

R _t = 11.00min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 60% isohexane, 40% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 35 ° C; detection: 235nm] .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.59 (s, 3H), 2.98-3.10 (m, 2H), 4.42 (br s, 2H), 5.09-5.18 (m, 1H), 5.30 (s , 2H), 6.90 (t, 1H), 7.01 (d, 1H), 7.19-7.30 (m, 3H), 7.32-7.44 (m, 4H), 7.59 (quint, 1H), 8.21 (d, 1H), 8.55 (d, 1H).

Example 19 Enantiomer-N- (1-aminopropyl-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3 -Carboxamide (Mirror Isomer A)

46 mg of the compound of Example 17 was separated into a mirror image isomer by preparative separation on the opposite palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 35 ° C, detection: 220nm].

The mirror isomer was repurified by preparative HPLC (RP18 column, mobile phase: Acetonitrile / water gradient (0.1% TFA). The product was concentrated, dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated.

Mirror isomer A: Yield: 7.3 mg (99% ee)

R _t = 8.59min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 45 ° C; detection: 235nm] .

LC-MS (Method 2): R _t = 0.56min (purity about 92%)

MS (ES +): m / z = 375 (M + H) ⁺

Example 20 Enantiomer-N- (1-aminopropyl-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3 -Carboxamide (Mirror Isomer B)

46 mg of the compound of Example 17 was separated into a mirror image isomer by preparative separation on the opposite palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 35 ° C, detection: 220nm].

Mirror isomer B: Yield: 13 mg (98.5% ee)

R _t = 10.57min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 45 ° C; detection: 235nm] .

LC-MS (Method 2): R _t = 0.57min (purity about 92%)

MS (ES +): m / z = 375 (M + H) ⁺

Example 21 Enantio-N- [2-amino-1- (2,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide

0.63 ml of a 2M solution of hydrochloric acid in ether (1.26 mmol) was added to 72 mg of enantio- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridin-3-yl} carbonyl) amino] -2- (2,4-difluorophenyl) ethyl} carbamate in third butyl ester (Example 81A, 0.13 mmol), and the mixture Stir at RT until overnight. The reaction mixture was diluted with ether and the precipitate was filtered. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the precipitate and the phases were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 51 mg of the title compound (84% of theory).

LC-MS (Method 2): R _t = 0.78min

MS (ES +): m / z = 473 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.69 (br s, 2H), 2.59 (s, 3H), 2.82-2.92 (m, 2H), 5.20 (t, 1H), 5.30 (s, 2H ), 6.90 (t, 1H), 7.02 (d, 1H), 7.05-7.11 (m, 1H), 7.18-7.28 (m, 3H), 7.50 (q, 1H), 7.59 (quint, 1H), 8.22 ( br s, 1H), 8.53 (d, 1H).

The examples shown in Table 3 were prepared similarly to Example 21.

table 3:

¹⁾ Prepared from Example 119A, (Mirror Isomer B)

²⁾ The starting material was dissolved in ether to form a 0.5M solution.

³⁾ Dissolve the starting material in 1,4-di The alkane forms a 0.2-0.5M solution.

^{4) The} reaction time is 2.5h.

Example 29 Enantiomer-N- (2-aminopropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine- 3-Carboxamide (Mirror Isomer A)

68 mg of Example 23 was separated on the opposite palm phase by a secondary preparation Mirror isomers:

1) Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 60% isohexane, 40% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 30 ° C, detection: 220nm.

2) Tubular column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 60% isohexane, 40% isopropanol + 0.2% diethylamine, flow rate: 15ml / min; 30 ° C, detection: 220nm .

Mirror isomer A: Yield: 21 mg (99% ee)

R _t = 10.15min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm] .

Example 30 Enantiomer-N- (2-aminopropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine- 3-Carboxamide (Mirror Isomer B)

68 mg of Example 23 was separated into the mirror isomers on the opposite palm phase by a secondary preparation:

1) Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 60% isohexane, 40% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 30 ° C, detection: 220nm.

2) Tubular column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 60% isohexane, 40% isopropanol + 0.2% diethylamine, flow rate: 15ml / min; 30 ° C, detection: 220nm .

Mirror isomer B: Yield: 21 mg (95% ee)

R _t = 9.31min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 80% isohexane, 20% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm] .

Example 31 Enantiomer-N- (2-aminopropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 -Carboxamide (Mirror Isomer A)

47mg of Example 25 was separated into mirror isomers on the opposite palm phase by secondary preparation:

1) Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm.

2) Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm .

Mirror isomer A: Yield: 13 mg (99% ee)

R _t = 7.00min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm] .

Example 32 Enantiomer-N- (2-aminopropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 -Carboxamide (Mirror Isomer B)

47mg of Example 25 was separated into mirror isomers on the opposite palm phase by secondary preparation:

1) Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm.

2) Column: Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm .

Mirror isomer B: Yield: 14 mg (97% ee)

R _t = 6.27min [Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm] .

Example 33 N- [2- (1-aminocyclohexyl) ethyl] -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a ] Pyridine-3-carboxamide

99 mg of racemic- (1- {2-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2- Methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] ethyl} cyclohexyl) carbamic acid third butyl trifluoroacetate (Example 93A, 0.14 mmol) was suspended in 0.67 ml In ether, 0.72 ml of a 2M solution of hydrochloric acid in ether (1.43 mmol) was added and the mixture was stirred at RT overnight. The precipitate was filtered and washed with ether, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added. After phase separation, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated and lyophilized. This gave 61 mg of the title compound (89% of theory).

LC-MS (Method 2): R _t = 0.80min

MS (ES +): m / z = 477 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.22-1.45 (m, 8H), 1.47-1.80 (m, 6H), 2.52 (s, 3H), 3.40 (t, 2H), 5.32 (s, 2H), 7.19 (s, 1H), 7.24 (t, 2H), 7.60 (quint, 1H), 8.55 (br s, 1H), 8.86 (s, 1H).

The example shown in Table 4 was prepared similarly to Example 33 by reacting a 10-20 equivalent solution of 2N hydrochloric acid in diethyl ether with the corresponding N-Boc compound under the reaction conditions described. The reaction time is 3h-5d.

If appropriate, purification was performed by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% trifluoroacetic acid) and / or silica gel chromatography (mobile phase gradient: dichloromethane / methanol). If appropriate, the product-containing fractions are concentrated and the residue is dissolved in ethyl acetate or dichloromethane / methanol and washed with a little saturated aqueous sodium bicarbonate solution. The organic phase was then dried over sodium sulfate and filtered and the filtrate was concentrated.

If appropriate, the reaction mixture is filtered from the precipitate and the precipitate is washed with ether and dried under high vacuum.

If appropriate, the reaction mixture is diluted with diethyl ether, the precipitate is filtered and ethyl acetate or dichloromethane and a saturated aqueous sodium bicarbonate solution are added to the filtrate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate was concentrated and dried under high vacuum.

Table 4:

Example 43 Racemic-N- [2-amino-1- (4-chlorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] pyridine- 3-carboxamide

2 ml of a 2M solution of hydrochloric acid in ether (4.0 mmol) was added to 107 mg of Example 83A (0.16 mmol), and the mixture was stirred at RT overnight. The precipitate was filtered, washed with diethyl ether, dissolved in dichloromethane containing a little methanol, washed twice with saturated aqueous sodium bicarbonate solution and Finally rinse with water. The organic phase was dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 61 mg of the title compound (85% of theory).

LC-MS (Method 2): R _t = 0.80min

MS (ES +): m / z = 441 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.02-1.14 (m, 2H), 1.16-1.38 (m, 3H), 1.48-1.89 (m, 8H), 2.62 (s, 3H), 2.84- 2.92 (m, 2H), 3.93 (d, 2H), 4.91-4.99 (m, 1H), 6.78 (d, 1H), 6.82 (t, 1H), 7.38-7.44 (m, 4H), 8.19 (br s , 1H), 8.46 (d, 1H).

Example 44 Racemic-N- (2-amino-1-phenylethyl) -8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] pyridine-3-carboxamide

2 ml of a 2M solution of hydrochloric acid in ether (4.0 mmol) was added to 70 mg of Example 82A (0.1 mmol), and the mixture was stirred at RT overnight. The precipitate was filtered, washed with diethyl ether, dissolved in a mixture of dichloromethane and a little methanol, washed twice with saturated aqueous sodium bicarbonate solution and finally washed with water. The organic phase was dried over sodium sulfate, filtered, concentrated and lyophilized. The product fractions were purified by thick layer chromatography (mobile phase: toluene / methanol = 10/1). This gave 31 mg of the title compound (73% of theory).

LC-MS (Method 7): R _t = 0.68min

MS (ES +): m / z = 407 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.03-1.14 (m, 2H), 1.16-1.37 (m, 3H), 1.63-2.20 (m, 8H), 2.63 (s, 3H), 2.85- 2.94 (m, 2H), 3.94 (d, 2H), 4.93-5.03 (m, 1H), 6.78 (d, 1H), 6.84 (t, 1H), 7.20-7.27 (m, 1H), 7.30-7.44 ( m, 4H), 8.19 (br s, 1H), 8.48 (d, 1H).

Example 45 Enantiomer-N- [2-amino-1- (2,4-difluorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] Pyridin-3-carboxamide

0.27 ml of a 2M solution of hydrochloric acid in ether (0.53 mmol) was added to 35 mg of Example 85A (0.05 mmol), and the mixture was stirred at RT overnight. The precipitate was filtered, washed with ether, dissolved in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and the filtrate was concentrated and lyophilized. This gave 23 mg of the title compound (93% of theory).

LC-MS (Method 7): R _t = 0.73min

MS (ES +): m / z = 443 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.02-1.13 (m, 2H), 1.14-1.36 (m, 3H), 1.63-1.99 (m, 8H), 2.62 (s, 3H), 2.83- 2.94 (m, 2H), 3.95 (d, 2H), 5.18-5.23 (m, 1H), 6.78 (d, 1H), 6.83 (t, 1H), 7.07-7.12 (m, 1H), 7.18-7.26 ( m, 1H), 7.50 (q, 1H), 8.12-8.28 (m, 1H), 8.47 (d, 1H).

Example 46 Racemic-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a ] Pyridine-3-carboxamide

1.5 ml of a 2M solution of hydrochloric acid in ether (3.0 mmol) was added to 198 mg of Example 84A (0.30 mmol), and the mixture was stirred at RT overnight. The precipitate was filtered, washed thoroughly with ether, dissolved in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered and the filtrate was concentrated and lyophilized. This gave 119 mg of the title compound (89% of theory).

LC-MS (Method 1): R _t = 1.04min

MS (ES +): m / z = 443 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.02-1.13 (m, 2H), 1.14-1.34 (m, 3H), 1.50-1.90 (m, 8H), 2.62 (s, 3H), 2.85- 2.94 (m, 2H), 3.95 (d, 2H), 4.92-4.99 (m, 1H), 6.79 (d, 1H), 6.83 (t, 1H), 7.20-7.28 (m, 1H), 7.36-7.49 ( m, 2H), 8.16 (br s, 1H), 8.48 (d, 1H).

Example 47 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -N- (2,3-dihydro-1H-indol-3-yl) -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

299 mg of Example 28 (69 mmol) was separated into mirror isomers on the palm phase by preparative separation [column: Daicel Chiralpak IA, 5 μm, 250 x 20 mm, mobile phase: 40% acetonitrile, 60% methanol, flow rate : 20ml / min; 25 ° C, detection: 230nm]. The product fraction was dissolved in acetonitrile / water and lyophilized.

Mirror isomer B: Yield: 91 mg (99% ee)

R _t = 4.87min [Chiralpak IA, 5 μm, 250 x 4.6mm; mobile phase: 50% acetonitrile, 50% methanol; flow rate 1.0ml / min; 30 ° C; detection: 220nm].

Example 48 Enantiomer -N- (1-aminopropyl-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridin-3-carboxamide

48 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] propyl} carbamic acid tert-butyl ester (Example 121A-Mirror image Structure A (0.1 mmol) was dissolved in 2.4 ml of diethyl ether, 0.49 ml of a 2M solution of hydrochloric acid in diethyl ether (0.98 mmol) was added and the mixture was stirred at RT overnight. Another 0.25 ml of a 2M solution of hydrochloric acid in diethyl ether was added, and the reaction solution was stirred at RT overnight. The mixture was then concentrated and the residue was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was concentrated. This gave 36 mg of the title compound (92% of theory).

LC-MS (Method 1): R _t = 0.71min

MS (ES +): m / z = 389 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.28 (d, 3H), 2.38 (s, 3H), 2.59 (s, 3H), 2.94-3.07 (m, 2H), 4.30 (quintet, 1H), 5.37 (s, 2H), 7.05-7.40 (m, 3H), 7.61 (quintet, 1H), 8.09 (br s, 3H), 8.51 (s, 1H).

Example 49 Racemic-6-chloro-8-[(2,6-difluorobenzyl) oxy] -N- (2,3-dihydro-1H-indol-3-yl) -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamide

141 mg of racemic-3-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3- Group} carbonyl) amino] indole-1-carboxylic acid third butyl ester (Example 104A, 0.25 mmol) was dissolved in 1.2 ml of diethyl ether. 24 ml of a 2M solution of hydrochloric acid in ether (2.48 mmol) was added and the mixture was dissolved in Stir at RT overnight. Then 1.24 ml of a 2M solution of hydrochloric acid in ether (2.48 mmol) was added, and the mixture was stirred at RT for 3 days. Then add 1.24ml of 2 at a time M hydrochloric acid in diethyl ether solution (2.48 mmol) and the mixture was stirred at reflux for 4 h (add additional ether and ether solution of hydrochloric acid in small portions at a time). The precipitate was filtered and washed thoroughly with diethyl ether, and then ethyl acetate and a saturated aqueous sodium bicarbonate solution were added. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated and lyophilized. This gave 93 mg of the title compound (80% of theory).

LC-MS (Method 2): R _t = 1.02min

MS (ES +): m / z = 469 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.49 (s, 3H), 3.31-3.40 (m, 1H), 3.73-3.81 (m, 1H), 5.33 (s, 2H), 5.61 (q, 1H), 5.68 (s, 1H), 6.56-6.63 (m, 2H), 7.02 (t, 1H), 7.18-7.28 (m, 4H), 7.60 (quintet, 1H), 8.50 (d, 1H) , 8.71 (s, 1H).

Example 50 Racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (1,2,3,4-tetrahydroquinolin-4-yl) imidazo [1 , 2-a] pyridine-3-carboxamide

229 mg of racemic-4-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -3,4-dihydroquinoline-1 (2H) -carboxylic acid third butyl ester (Example 105A, 0.41 mmol) was dissolved in 10 ml of diethyl ether, and 2.05 ml of a 2 M solution of hydrochloric acid in diethyl ether (4.09 mmol ) And the mixture was stirred at RT overnight. Then another 1.02 ml of 2M hydrochloric acid in diethyl ether was added, and the mixture was stirred at RT overnight. A little ether was added to the reaction mixture and the resulting solid was filtered off and washed with ether. Dissolve the solid in dichloromethane with a little methanol And washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% TFA). The product fractions were concentrated, treated in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 140 mg of the title compound (75% of theory).

LC-MS (Method 2): R _t = 0.83min

MS (ES +): m / z = 449 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.92-2.05 (m, 2H), 2.50 (s, 3H), 3.20-3.29 (m, 2H), 5.20 (q, 1H), 5.31 (s, 2H), 5.87 (s, 1H), 6.46-6.54 (m, 2H), 6.89-6.94 (m, 2H), 7.00 (d, 1H), 7.10 (d, 1H), 7.23 (t, 2H), 7.59 (Quintet, 1H), 8.27 (d, 1H), 8.58 (d, 1H).

Example 51 Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Imidazo [1,2-a] pyridine-3-carboxamide

120 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -2- (3,4-difluorophenyl) ethyl} third butyl formate (Example 107A, 0.20 mmol) was dissolved in 2 ml of ether, and 1 ml of a 2 M solution of hydrochloric acid in ether was added. (2 mmol) and the mixture was stirred at RT overnight. Then add another 1ml of 2M hydrochloric acid Ether solution, and the mixture was stirred at RT overnight. The reaction mixture was filtered and washed with diethyl ether. The solid was dissolved in dichloromethane with a little methanol and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated, treated in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 82 mg of the title compound (84% of theory).

LC-MS (Method 2): R _t = 0.81min

MS (ES +): m / z = 487 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.29 (s, 3H), 2.52 (s, 3H), 2.88-3.00 (m, 2H), 4.93-5.05 (m, 1H), 5.29 (s, 2H), 6.90 (s, 1H), 7.19-7.28 (m, 3H), 7.36-7.49 (m, 2H), 7.59 (quintet, 1H), 8.17 (br s, 1H), 8.38 (s, 1H ).

Example 52 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (1,2,3,4-tetrahydroquinolin-4-yl) imidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

132 mg of Example 50 was separated into mirror isomers by preparative separation on the counter palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 15ml / min; 45 ° C, detection: 220nm].

Mirror isomer B: Yield: 64mg (99% ee)

R _t = 8.05min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 53 Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2- Methyl-imidazo [1,2-a] pyridine-3-carboxamide

12.5 ml of a 2 M solution of hydrochloric acid in ether was added to 148 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [ 1,2-a] pyridin-3-yl} carbonyl) amino] -2- (3,4-difluorophenyl) ethyl} carbamic acid third butyl ester (Example 106A; 0.251 mmol), and The mixture was stirred at RT until overnight. The reaction precipitate was filtered, washed with diethyl ether, treated in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The combined organic phases were dried over magnesium sulfate and concentrated. The residue was dissolved in methanol and purified by preparative HPLC (Method 9). This gave 63 mg (51% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.87min

MS (ES +): m / z = 491.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.61 (br.s, 2H), 2.58 (s, 3H), 3.38-3.42 (d, 2H), 4.91 (t, 1 H); 5.32 (s , 2 H); 7.20-7.26 (m, 4 H); 7.34-7.46 (m, 2 H); 7.59 (quint, 1H), 8.21 (br.s, 1H), 8.61 (d, 1H).

The examples shown in Table 5 were prepared similarly to Example 53.

Example 61 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N-[(3S) -pyrrolidin-3-yl] imidazo [1,2-a] pyridine-3-carboxyl Amidine

130 mg of (3S) -3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amino] pyrrolidine-1-carboxylic acid benzyl ester (Example 115A; 0.250 mmol) was first placed in 60 ml of ethanol, and 17.5 mg of 20% palladium (II) hydroxide (0.025 mmol, 0.1 equivalent) was added and the mixture was Hydrogenated under standard hydrogen pressure for two hours. The reaction mixture was filtered and concentrated and the residue was purified by preparative HPLC. This gives 42 mg (44% of theory) of the title compound Thing.

LC-MS (Method 2): R _t = 0.50min

MS (ES +): m / z = 387.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.60-1.70 (m, 1 H); 1.95-2.05 (m, 1 H); 2.55 (s, 3 H; overlap with DMSO signal); 2.61-2.80 (m, 2 H); 2.88-3.03 (m, 2 H); 4.28-4.37 (m, 1 H); 5.30 (s, 2 H); 6.90 (t, 1 H); 6.99 (d, 1 H) ; 7.21 (t, 2 H); 7.60 (q 1 H); 7.81 (d, 1 H); 8.51 (d, 1 H).

Example 62 Enantio-N- [2-amino-2- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide

160 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -1- (3,4-difluorophenyl) ethyl} benzyl carbamate (intermediate 117A; 0.264 mmol) was first placed in 150 ml of ethanol, and 100 mg of 10% activated carbon on palladium was added and The mixture was hydrogenated under standard hydrogen pressure for two hours. The reaction mixture was filtered and the filtrate was concentrated. This gave 123 mg (99% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.67min

MS (ES +): m / z = 373.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.33 (s, 3 H); 3.40-3.51 (m, 2 H); 4.08 (t, 1 H); 5.30 (s, 2 H); 6.88 ( t, 1 H); 7.00 (d, 1 H); 7.19-7.24 (m, 3 H); 7.32 (q, 1 H); 7.48 (dd, 1 H); 7.56 (q, 1 H); 7.80 ( t, 1 H); 8.51 (d, 1 H).

Example 63 Racemic-N- (1-amino-3-isopropoxyprop-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide

305 mg of racemic- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] -3-isopropoxypropyl} benzyl carbamate (intermediate 116A; 0.54 mmol) was first placed in 46 ml of ethanol, 44 mg of 10% activated carbon on palladium was added and the mixture was in standard hydrogen Hydrogenated under atmospheric pressure for 4 hours. The reaction mixture was filtered and concentrated and the residue was purified by preparative HPLC (column: Macherey-Nagel VP 50/21 Nucleodur 100-5 C18 HTEC, 50x21 mm; mobile phase: aqueous ammonia with gradient of 0.1% concentration and methanol). This gave 127 mg of the title compound (54% of theory).

LC-MS (Method 2): R _t = 0.59min

MS (ES +): m / z = 433.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.10 (d, 6 H), 1.74 (br.s, 2 H), 2.54 (s, 3 H; overlap with DMSO signal), 2.72 (d, 2 H), 3.49 (d, 2 H), 3.58 (q, 1 H), 3.99 (m, 1 H), 5.30 (s, 2 H), 6.93 (t, 1 H), 7.00 (d, 1 H) , 7.23 (t, 2 H), 7.53 (br.s, 1 H), 7.59 (q, 1 H), 8.60 (d, 1 H).

Example 64 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N-[(2R) -1- (morpholin-4-yl) hex-2-yl] imidazole Benzo [1,2-a] pyridine-3-carboxamide

59 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N-[(2R) -1-oxohex-2-yl] imidazo [1,2-a ] Pyridine-3-carboxamide (0.12 mmol, 1 equivalent) was suspended in 0.6 ml of dichloromethane, 13.3 μl of morpholine (0.132 mmol, 1.1 equivalent) was added and the mixture was stirred at RT for 3 h. 35.7 mg of sodium triacetoxyborohydride (0.168 mmol, 1.4 equivalents) was added, and the reaction mixture was stirred at RT overnight. A 1 N aqueous sodium hydroxide solution was added and the reaction mixture was extracted three times with dichloromethane. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in methanol and purified by preparative HPLC (Method 9). 22.4 mg (36% of theory) of the desired compound was concentrated to a glassy solid.

LC-MS (Method 2): R _t = 0.81

MS (ES +): m / z = 487.4 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88 (t, 3H), 1.20-1.62 (m, 6H), 2.30-2.40 (m, 2 H), 2.54 (s + m, 3 + 4H, Covered by DMSO signal), 3.50-3.60 (m, 4 H), 4.13-4.24 (m, 1H), 5.31 (s, 2H), 6.92 (t, 1H), 6.99 (d, 1H), 7.23 (t, 2H), 7.59 (q, 1H), 7.63 (d, 1 H), 8.50 (d, 1H).

The examples shown in Table 6 were prepared similarly to Example 64.

Table 6:

Example 71 8-[(2,6-difluorobenzyl) oxy] -N- (9-ethyl-9-azabicyclo [3.3.1] non-3-yl) -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide

60 mg of N- (9-azabicyclo [3.3.1] non-3-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (Example 27, 0.14 mmol) was first placed in 1.4 ml of anhydrous THF, 4.2 mg of sodium hydride (purity 95%, 0.16 mmol) was added, and the mixture was stirred at RT for 15 min. Then 0.011 ml of ethyl iodoethane (0.14 mmol) was added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was concentrated and dried. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and filtered and the filtrate was concentrated and lyophilized. This gave 35 mg of the title compound (55% of theory).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 469 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.97 (t, 3H), 1.50 (d, 2H), 1.60-1.97 (m, 8H), 2.50 (s, 3H), 2.69 (q, 2H) , 2.96 (s, 2H), 4.63-4.79 (m, 1H), 5.30 (s, 2H), 6.91 (t, 1H), 6.99 (d, 1H), 7.23 (t, 2H), 7.59 (Fivefold Peak , 1H), 7.71 (d, 1H), 8.52 (d, 1H).

Example 72 N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3- Carboxamide

100 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (0.31 mmol), 151 mg of (benzotris Azole-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 0.47 mmol) and 127 mg of 4-methylmorpholine (1.26 mmol) were first placed in 2 ml of DMF. 55 mg of 2-methylpropan-1,2-diamine (0.63 mmol) were then added and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The crude product was treated in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated and lyophilized. This gave 80 mg of the title compound (66% of theory).

LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 389 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.08 (s, 6H), 2.00 (br s, 2H), 2.52 (s, 3H), 3.22 (d, 2H), 5.30 (s, 2H), 6.91 (t, 1H), 7.01 (d, 1H), 7.23 (t, 2H), 7.59 (five-fold peak, 1H), 7.74 (br s, 1H), 8.64 (d, 1H).

Example 73 N- (2-amino-2-methylpropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] Pyridin-3-carboxamide

70 mg of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (0.20 mmol), 96 mg ( Benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 0.30 mmol) and 80 mg of 4-methylmorpholine (0.79 mmol) were first placed in 1 ml of DMF . 35 mg of 2-methylpropan-1,2-diamine (0.40 mmol) were then added and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product was treated in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated and lyophilized. This gave 38 mg of the title compound (45% of theory).

LC-MS (Method 1): R _t = 0.88min

MS (ES +): m / z = 423 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6H), 2.04 (br s, 2H), 2.50 (s, 3H), 3.22 (d, 2H), 5.35 (s, 2H), 7.20 (d, 1H), 7.24 (t, 2H), 7.61 (five-fold peak, 1H), 7.80 (br s, 1H), 8.75 (d, 1H).

Example 74 N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine -3-carboxamide

100 mg of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (0.30 mmol), 145 mg of ( Benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 0.45 mmol) and 122 mg of 4-methylmorpholine (1.20 mmol) were first placed in 1.9 ml of DMF in. 53 mg of 2-methylpropan-1,2-diamine (0.60 mmol) were then added and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 94 mg of the title compound (78% of theory).

LC-MS (Method 2): R _t = 0.61min

MS (ES +): m / z = 403 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6H), 1.53 (br s, 2H), 2.31 (s, 3H), 2.52 (s, 3H), 3.20 (d, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.24 (t, 2H), 7.59 (quintet, 1H), 7.64-7.72 (m, 1H), 8.47 (s, 1H).

Example 75 Racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (1,2,3,4-tetrahydroquinolin-3-yl) imidazo [1 , 2-a] pyridine-3-carboxamide

70 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (0.22 mmol), 54 mg of (benzotris Azole-1-yloxy) bisdimethylaminomethylium fluoroborate (TBTU, 0.26 mmol) and 133 mg of 4-methylmorpholine (1.32 mmol) were first placed in 1.5 ml of dichloromethane . After 10 min at RT, 53 mg of 1,2,3,4-tetrahydroquinolin-3-amine (0.24 mmol) was added and the mixture was stirred at RT overnight. About 5 ml of water was added, the reaction solution was stirred for another 30 min and the resulting precipitate was filtered, washed thoroughly with water and dried under high vacuum. The crude product was purified by preparative thin layer chromatography (dichloromethane / methanol 20: 1). This gave 52 mg of the title compound (52% of theory).

LC-MS (Method 2): R _t = 0.88min

MS (ES +): m / z = 449 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.39 (s, 3H), 2.79-2.88 (m, 1H), 2.91-2.99 (m, 1H), 3.09-3.18 (m, 1H), 3.32- 3.40 (m, 1H), 4.21-4.30 (m, 1H), 5.30 (s, 2H), 5.70 (s, 1H), 6.47 (t, 1H), 6.51 (d, 1H), 6.90 (d, 2H) , 6.93 (t, 1H), 7.01 (d, 1H), 7.23 (t, 2H), 7.59 (five-fold peak, 1H), 7.63 (d, 1H), 8.61 (d, 1H).

The example shown in Table 7 was prepared similarly to Example 75 by reacting an appropriate carboxylic acid with an appropriate commercially available amine under the reaction conditions described in Representative Procedure 2.

Table 7:

^a) There is a second type of chromatographic separation: [column: Sunfire C18, 5μm, 250 x 20mm, mobile phase: 60% water, 35% methanol + 5% 1% TFA solution, flow rate: 25ml / min; 25 ℃, detection: 210nm].

Example 81 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (1,2,3,4-tetrahydroquinolin-3-yl) imidazo [1, 2-a] pyridine-3-carboxamide (mirromeric isomer A)

38 mg of Example 75 was separated into mirror isomers by preparative separation on the counter palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 15ml / min; 40 ° C, detection: 220nm].

Mirror isomer A: Yield: 18 mg (99% ee)

R _t = 5.75min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 82 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl) imidazo [1,2- a] pyridine-3-carboxamide

Place 18.8 mg (0.12 mmol) of 2,2,6,6-tetramethylpiperidine-4-amine, and add 32 mg (0.10 mmol) of 8-[(2,6-difluorobenzyl) oxy Methyl] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid in 0.4 ml of DMF solution and 42 mg (0.13 mmol) of (benzotriazol-1-yloxy) bisdimethyl 0.2 ml of DMF solution of aminoaminomethylium fluoroborate (TBTU). Then 20 mg (0.20 mmol) of 4-methylmorpholine was added and the reaction was stirred at RT overnight. The mixture was then filtered and the filtrate was purified by preparative LC-MS (Method 12). The product-containing fractions were concentrated under reduced pressure. This gave 27 mg (59% of theory) of the target product.

LC-MS (Method 8): R _t = 0.69min; MS (ESI +): m / z = 457 (M + H) ⁺

The examples shown in Table 8 were prepared similarly to Example 82.

Example 93 Enantiomer-N- (1-amino-3-isopropoxyprop-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirromeric isomer A)

114 mg of Example 63 was dissolved in 2.5 ml of ethanol and separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol , Flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: mirror isomer A: 44 mg (100% ee)

Mirror isomer A: R _t = 4.33min [Daicel Chiralpak OD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.10 (d, 6 H), 1.68 (br.s, 2 H), 2.54 (s, 3 H; overlaps with DMSO signal), 2.72 (d, 2 H), 3.49 (d, 2 H), 3.58 (q, 1 H), 3.99 (m, 1 H), 5.30 (s, 2 H), 6.91 (t, 1 H), 7.01 (d, 1 H) , 7.23 (t, 2 H), 7.53 (br.s, 1 H), 7.58 (q, 1 H), 8.60 (d, 1 H).

Example 94 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- {2-methyl-2-[(2,2,2-trifluoroethyl) amino ] Propyl} imidazo [1,2-a] pyridine-3-carboxamide

100 mg (0.25 mmol) of N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (Example 74) was first placed in 2 ml of DMF, 0.041 ml (0.25 mmol) of trichloromethanesulfonic acid 2,2,2-trifluoroethyl ester, 69 mg (0.50 mmol) of potassium carbonate and 4.1 mg (0.025 mmol) of potassium iodide and then the mixture was stirred at RT overnight. Then 0.082 ml (0.50 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate was added and the mixture was stirred again at RT overnight. An additional 0.123 ml (0.75 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate was added and the mixture was stirred again at RT overnight. For subsequent processing, 1 ml of water was added, the mixture was filtered through an Extrelut filter, dissolved in dichloromethane, and the filtrate was concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.5% ammonium hydroxide). The product fractions were combined, evaporated and dried under high vacuum.

Yield: 48 mg (38% of theory)

LC-MS (Method 2): R _t = 0.96min

MS (ES +): m / z = 485.4 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6H), 2.31 (s, 3H), 2.37 (t, 1H), 2.54 (s, 3H; hidden by DMSO signal), 3.18-3.30 (m, 4H), 5.28 (s, 2H), 6.92 (s, 1H), 7.19-7.29 (m, 2H), 7.50 (t, 1H), 7.54-7.64 (m, 1H), 8.50 (s, 1H ).

Example 95 Enantiomer-N- (3-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine Pyridin-3-carboxamide dihydrochloride (mirromeric isomer A)

68 mg of enantiomer- {3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amino] -2-methylpropyl} carbamic acid tert-butyl ester (Example 213A, 0.14 mmol, 1 equivalent) dissolved in 2 ml of 4N hydrochloric acid A solution of alkane (1.4 mmol, 10 eq.) And stirred at RT overnight. The mixture was then concentrated and dried under reduced pressure. This gave 48 mg (75% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.56min

MS (ES +): m / z = 389.2 (M-2HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.99 (d, 3 H), 2.05-2.17 (m, 1 H), 2.62 (s, 3 H), 2.65-2.75 (m, 1 H), 2.83-2.93 (m, 1 H), 3.32 (t, 2 H), 5.43 (s, 2 H), 7.21-7.37 (m, 3 H), 7.47 (br.s, 1 H), 7.56-7.68 ( m, 1 H), 7.98 (br.s, 3 H), 8.56 (br.s, 1 H), 8.68 (d, 1 H).

Example 96 Enantiomer-N- (3-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine -3-Carboxamidamine Dihydrochloride (Mirror Isomer B)

79 mg of enantiomer- {3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amino] -2-methylpropyl} carbamic acid third butyl ester (Example 214A, 0.16 mmol, 1 equivalent) dissolved in 2 ml of 4N hydrochloric acid A solution of alkane (1.6 mmol, 10 eq.) And stirred at RT overnight. The mixture was then concentrated and dried under reduced pressure. This gave 66 mg (88.5% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 389.2 (M-2HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.99 (d, 3 H), 2.06-2.19 (m, 1 H), 2.63 (s, 3 H), 2.66-2.75 (m, 1 H), 2.83-2.94 (m, 1 H), 3.31 (t, 2 H), 5.43 (s, 2 H), 7.26 (t, 2 H), 7.36 (br.s, 1 H), 7.48-7.67 (m, 2 H), 8.03 (br.s, 2 H), 8.62 (br.s, 1 H), 8.71 (d, 1 H).

Example 97 Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-{[(2,6-difluorophenyl) ( ² H ₂ ) methyl] oxy Yl} -2-methylimidazo [1,2-a] pyridine-3-carboxamide

At RT, 250 mg of enantiomer- [2- (3,4-difluorophenyl) -2-{[(8-{[(2,6-difluorophenyl) ( ² H ₂ ) methyl] oxy} -2-methylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino} ethyl] third butyl formate (Example 170A, 0.44 mmol, 1 equivalent) was dissolved in 4.4 ml 4N hydrochloric acid A solution of alkane (17.4 mmol, 40 equivalents), and the mixture was stirred at RT for 3 h. The mixture was then concentrated, water and saturated aqueous ammonia were added to the residue and the mixture was extracted four times with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product obtained in this way is applied to the Extrelut ^® silica gel was filtered off and purified to the heart (Biotage SNAP Cartridge KP-Sil 10g , mobile phase: dichloromethane / methanol: from 95: 5 to 0: 100). This gave 198 mg (95% of theory; 99% purity) of the title compound.

LC-MS (Method 7): R _t = 0.71min

MS (ES +): m / z = 475.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.70 (br.s, 2 H), 2.59 (s, 3 H), 2.86-2.94 (m, 2 H), 4.92-5.01 (m, 1 H ), 6.91 (t, 1 H), 7.01 (d, 1 H), 7.20-7.28 (m, 3 H), 7.36-7.50 (m, 2 H), 7.54-7.63 (m, 1 H), 8.18 ( br.s, 1 H), 8.53 (d, 1 H).

Example 98 Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2-fluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide

At RT, add 0.8ml of 4N hydrochloric acid A solution of alkane (3.1 mmol, 10 equivalents) was added to 191 mg of enantiomer- {2- (3,4-difluorophenyl) -2-[({8-[(2-fluorobenzyl) oxy] -2 -Methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] ethyl} carbamic acid third butyl ester (Example 197A, 0.3 mmol, 1 equivalent). The mixture was stirred at RT overnight and then concentrated. The residue was treated in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated. This gave 101 mg (69% of theory; 97% purity) of the title compound.

LC-MS (Method 7): R _t = 0.69min

MS (ES +): m / z = 455.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.70 (br.s, 2 H); 2.61 (s, 3 H), 2.83-2.93 (m, 2 H), 4.96 (t, 1 H), 5.33 (s, 2 H), 6.92 (t, 1 H), 6.99 (d, 1 H), 7.19-7.34 (m, 3 H), 7.35-7.53 (m, 3 H), 7.62 (t, 1 H ), 8.20 (br.s, 1 H), 8.51 (d, 1 H).

The examples shown in Table 9 were prepared similarly to Example 98 from appropriate Boc-protected amines.

¹⁾ No solvent was added to the reaction, and 20 equivalents of 4M hydrochloric acid in 1,4-bis were used. Alkane solution

Example 104 N- (3-amino-3-methylbutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] Pyridin-3-carboxamide

118 mg of 4-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amine] -2-methylbut-2-yl} carbamic acid third butyl trifluoroacetate (Example 179A, 0.22 mmol, 1 equivalent) was first placed in 4 ml of a 2N hydrochloric acid in ether solution (8 mmol, 36 equivalents) ) And stir overnight at RT. The resulting precipitate was filtered, washed thoroughly with ether and then dissolved in ethyl acetate. The organic phase was washed twice with a saturated aqueous sodium bicarbonate solution and with water. The aqueous phase was extracted twice with dichloroethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. thus This gave 65.5 mg (68% of theory, 99% purity) of the target compound.

LC-MS (Method 2): R _t = 0.75min

MS (ES +): m / z = 437.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.09 (s, 6 H), 1.59 (t, 2 H), 2.10 (br.s, 2 H), 3.40 (t, 2 H), 5.33 ( s, 2 H), 7.20 (d, 1 H), 7.26 (t, 2 H), 7.55-7.65 (m, 1 H), 8.42 (br.s, 1 H), 8.84 (d, 1 H), [Another signal is hidden under the solvent peak].

The compounds listed in Table 10 were prepared similarly to Example 104 from the appropriate Boc-protected amine. Use 10-40 equivalents of 2N hydrochloric acid. For subsequent processing of the reaction, any solids formed were dissolved in ethyl acetate or dichloromethane / methanol and further processed in a similar manner.

^{1) The} reaction was performed using 10 equivalents of a 2M solution of hydrochloric acid in diethyl ether.

^{2) The} reaction was carried out using 56 equivalents of a 2M solution of hydrochloric acid in ether.

^{3) The} reaction was performed using 31 equivalents of a 2M solution of hydrochloric acid in diethyl ether.

Example 120 N-[(3S) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine- 3-carboxamide

155 mg of {(2S) -3-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3 -Yl} carbonyl) amino] but-2-yl} carbamic acid benzyl ester (Example 191A, 0.28 mmol, 1 equivalent) was dissolved in 50 ml of ethanol, and 40 mg of palladium (5%) on activated carbon was added. The mixture was hydrogenated at RT and standard pressure for 3 h. After the reaction was completed, the mixture was filtered through silica gel, the residue was washed with ethanol and the mother liquor was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC (Method 9).

LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 389.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.01 (d, 3 H), 1.15 (d, 3 H), 1.80 (br.s, 2 H), 2.50 (s, 3 H; and DMSO signal Overlapping), 2.82-2.96 (m, 1 H), 3.81-3.95 (m, 1 H), 5.30 (s, 2 H), 6.92 (t, 1 H), 7.01 (d, 1 H), 7.23 (t , 2 H), 7.47-7.54 (m, 1 H), 7.55-7.63 (m, 1 H), 8.64 (d, 1 H).

Example 121 N-[(3R) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine- 3-carboxamide

235 mg of {(2R) -3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl ) Amino] but-2-yl} carbamic acid benzyl ester (Example 184A, 0.45 mmol, 1 equivalent) was dissolved in 260 ml of ethanol, and 63 mg of activated carbon (10%, 0.45 mmol, 1 equivalent) was added . The mixture was hydrogenated at RT and atmospheric pressure for 1.5 h and then filtered through silica gel and concentrated. The residue was dissolved in methanol and purified by preparative HPLC (Method 9). This gave 96 mg (55% of theory) of the title compound.

Diastereomer ratio 3: 1

Major diastereomers: LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 389.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.01 (d, 3 H), 1.15 (d, 3 H), 1.65 (br.s, 2 H), 2,51 (s, 3 H; and DMSO signals overlap), 2.82-2.96 (m, 1 H), 3.81-3.95 (m, 1 H), 5.30 (s, 2 H), 6.92 (t, 1 H), 7.01 (d, 1 H), 7.23 (t, 2 H), 7.47-7.54 (m, 1 H), 7.55-7.63 (m, 1 H), 8.64 (d, 1 H).

Example 122 Enantiomer-N- (1-amino-3-methoxyprop-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide di-trifluoroacetate (mirror isomer A)

58 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) Amino] -3-methoxypropyl} benzyl carbamate (Example 210A, Mirror Isomer A, 0.1 mmol, 1 equivalent) was dissolved in 10 ml of ethanol, and 10 mg of activated carbon was added to palladium hydroxide (10%). The mixture was hydrogenated at RT and atmospheric pressure for 3 h and then filtered through silica gel. The residue was washed with ethanol, ethyl acetate and dichloromethane and the organic phase was concentrated. The residue was purified by preparative HPLC (column: Sunfire C18, 5 μm, 250 x 20 mm, flow rate: 25 ml, wavelength: 210 nm, temperature 40 ° C., mobile phase: acetonitrile: water + 1% TFA = 20: 80). This gave 27 mg (43% of theory, 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 405.3 (M-2TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.91-3.03 (m, 1 H), 3.05-3.16 (m, 1 H), 3.32 (s, 3 H), 3.45-3.54 (m, 2 H ), 4.36-4.51 (m, 1 H), 5.33 (s, 2 H), 7.05-7.12 (m, 1 H), 7.15-7.20 (m, 1 H), 7.24 (t, 2 H), 7.53- 7.65 (m, 1 H), 7.85 (br.s, 4 H), 8.62 (d, 1 H), [additional signal is hidden under the solvent peak].

Example 123 Enantiomer-N- (1-amino-3-methoxyprop-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamidine di-trifluoroacetate (mirror isomer B)

Similar to Example 122, 53 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -3-methoxypropyl} benzyl carbamate (Example 211A, mirror isomer B, 0.1 mmol, 1 equivalent) was hydrogenated and subsequently processed. This gave 22 mg (36% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 405.3 (M-2TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.91-3.03 (m, 1 H), 3.05-3.16 (m, 1 H), 3.32 (s, 3 H), 3.45-3.54 (m, 2 H ), 4.36-4.51 (m, 1 H), 5.33 (s, 2 H), 7.05-7.12 (m, 1 H), 7.15-7.20 (m, 1 H), 7.24 (t, 2 H), 7.53- 7.65 (m, 1 H), 7.85 (m, 4 H), 8.62 (d, 1 H), [additional signal is hidden under the solvent peak].

Example 124 Enantio-N- [1-amino-3- (3,4-difluorophenoxy) prop-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2- Methyl-imidazo [1,2-a] pyridine-3-carboxamide di-trifluoroacetate

Similar to Example 122, 110 mg of enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -3- (3,4-difluorophenoxy) propyl} benzyl carbamate (Example 212A, mirror image isomer B) was hydrogenated and subsequently processed. This gave 69 mg (55% of theory; 100% purity) of the title compound.

LC-MS (Method 2): R _t = 0.87min

MS (ES +): m / z = 503.2 (M-2TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 3.03-3.15 (m, 1 H), 3.16-3.27 (m, 1 H), 4.12-4.22 (m, 2 H), 4.58-4.70 (m, 1 H), 5.33 (s, 2 H), 6.80-6.87 (m, 1 H), 7.01-7.09 (m, 1 H), 7.10-7.19 (m, 2 H), 7.24 (t, 2 H), 7.34-7.44 (m, 1 H), 7.54-7.64 (m, 1 H), 7.88-8.05 (m, 4 H), 8.62 (d, 1 H), [additional signals are hidden under the solvent peak].

Example 125 Racemic-N- (3-azabicyclo [4.1.0] hept-1-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide

Similar to Example 121, 216 mg of racemic-1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -3-azabicyclo [4.1.0] hepta-3-carboxylic acid benzyl ester (Example 176A, 0.4 mmol, 1 equivalent) reaction [0.2 equivalent of palladium on activated carbon (10%) , Reaction: 16h] and subsequent treatment [after separation by HPLC, the residue was treated in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated]. This gave 123 mg (74% of theory; 98%) of the title compound.

LC-MS (Method 7): R _t = 0.56min

MS (ES +): m / z = 413.1 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.92 (t, 1 H), 0.96-1.02 (m, 1 H), 1.22-1.31 (m, 1 H), 1.57-1.68 (m, 1 H ), 2.01-2.11 (m, 1 H), 2.45 (s, 3 H), 2.59-2.76 (m, 2 H), 3.19-3.29 (m, 2 H), 5.30 (s, 2 H), 5.79 ( br.s, 1 H), 6.94 (t, 1 H), 7.02 (d, 1 H), 7.23 (t, 2 H), 7.53-7.63 (m, 1 H), 8.24 (s, 1 H), 8.60 (d, 1 H).

Example 126 Enantiomer-N- (2-amino-4,4,4-trifluorobutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

Under argon, 170 mg of enantio- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3 -Yl} carbonyl) amino] -4,4,4-trifluorobut-2-yl} benzyl carbamate (Example 215A, 0.30 mmol, 1 equivalent) was first placed in 3 ml of ethanol / dichloroethane ( In 2/1), 31 mg of activated carbon on palladium (10%) and 0.60 ml (5.90 mmol, 20 equivalents) of cyclohexene were added and the mixture was stirred under reflux overnight. The reaction solution was filtered through a Millipore® filter, washed thoroughly with ethanol / dichloroethane (2/1), concentrated and dried under high vacuum. The product was purified by silica gel chromatography (mobile phase: dichloromethane / methanol: 40/1 isocratic). This gave 92 mg (67% of theory; 95%) of the title compound.

LC-MS (Method 7): R _t = 0.62min

MS (ES +): m / z = 443.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.85 (br.s, 2 H), 2.15-2.38 (m, 1 H), 2.40-2.47 (m, 1 H), 3.15-3.28 (m, 2 H), 5.30 (s, 2 H), 6.94 (t, 1 H), 7.01 (d, 1 H), 7.24 (t, 2 H), 7.54-7.64 (m, 1 H), 7.89 (t, 1 H), 8.64 (d, 1 H), [the additional signal is hidden under the solvent peak].

Example 127 Enantiomer-N- (2-amino-4,4,4-trifluorobutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

Similar to Example 126, 172 mg of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -4,4,4-trifluorobut-2-yl} benzyl carbamate trifluoroacetate (Example 216A, 0.30 mmol, 1 equivalent) was reacted and subsequently processed. This gave 66 mg (50% of theory; 95%) of the title compound.

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 443.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.80 (br.s, 2 H), 2.15-2.37 (m, 1 H), 2.40-2.47 (m, 1 H), 3.15-3.28 (m, 2 H), 5.30 (s, 2 H), 6.94 (t, 1 H), 7.01 (d, 1 H), 7.24 (t, 2 H), 7.55-7.64 (m, 1 H), 7.89 (t, 1 H), 8.64 (d, 1 H), [the additional signal is hidden under the solvent peak].

Example 128 Enantiomer-N- (2-amino-4,4,4-trifluorobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

85 mg of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -4,4,4-trifluorobut-2-yl} benzyl carbamate (Example 217A, 0.14 mmol, 1 equivalent) was first placed in 2.1 ml of 1: 1: 0.1 ethanol / di To a mixture of methyl chloride / methanol, 0.3 ml of cyclohexene (2.88 mmol, 20 equivalents) and 15 mg of 10% activated carbon on palladium (0.014 mmol, 0.1 equivalent) were added, and the mixture was stirred under reflux for 3 h. Then another 0.15 ml of cyclohexene (1.44 mmol, 10 equivalents) and 15 mg of 10% activated carbon on palladium (0.014 mmol, 0.1 equivalent) were added, and the mixture was stirred at reflux for another 6 h. The reaction solution was filtered through a Millipore® filter, washed thoroughly with methanol and concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The crude product was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 52 mg (75% of theory, 95% purity) of the title compound.

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 457.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.69 (br.s, 2 H), 2.16-2.30 (m, 1 H), 2.31 (s, 3 H), 2.36-2.46 (m, 1 H ), 3.13-3.27 (m, 2 H), 5.27 (s, 2 H), 6.92 (s, 1 H), 7.23 (t, 2 H), 7.54-7.65 (m, 1 H), 7.81-7.88 ( m, 1 H), 8.47 (s, 1 H), [another signal is hidden under the solvent peak].

Specific optical rotation [α] (365nm, 19.6 ℃) = + 42.5 ° (c = 0.00445g / ml, acetonitrile)

Example 129 Enantiomer-N- (2-amino-4,4,4-trifluorobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

92 mg of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl } Carbonyl) amino] -4,4,4-trifluorobut-2-yl} benzyl carbamate (example 218A, 0.16 mmol, 1 equivalent) was first placed in 2.1 ml of 1: 1: 0.1 ethanol / di To a mixture of methyl chloride / methanol, 0.47 ml of cyclohexene (4.67 mmol, 30 equivalents) and 33 mg of 10% activated carbon on palladium (0.03 mmol, 0.1 equivalent) were added, and the mixture was stirred under reflux for 6 h. The reaction solution was filtered through a Millipore® filter, washed thoroughly with methanol and concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The crude product was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 46 mg (64% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.70min

MS (ES +): m / z = 457.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.71 (br.s, 2 H), 2.16-2.30 (m, 1 H), 2.31 (s, 3 H), 2.36-2.46 (m, 1 H ), 3.13-3.27 (m, 2 H), 5.28 (s, 2 H), 6.92 (s, 1 H), 7.23 (t, 2 H), 7.54-7.65 (m, 1 H), 7.81-7.88 ( m, 1 H), 8.47 (s, 1 H), [another signal is hidden under the solvent peak].

Specific rotation [α] (365nm, 19.5 ℃) =-39.0 ° (c = 0.005g / ml, acetonitrile)

The examples shown in Table 11 were prepared similarly to Example 75 by reacting a suitable carboxylic acid with a suitable commercially available amine under the reaction conditions described in Representative Procedure 2.

Example 140 N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] Pyridin-3-carboxamide

45 mg of 8-[(2,6-difluorobenzyl) oxy] -6-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (0.13 mmol, 1 (Equivalent), 65 mg of (benzotriazol-1-yloxy) bisdimethylamino-methylium fluoroborate (TBTU, 0.2 mmol, 1.5 equivalents), and 54 mg of 4-methylmorpholine ( 0.54 mmol, 4 equivalents) was first placed in 0.9 ml of DMF. After 10 min at RT, 24 mg of 1,2-diamino-2-methylpropane (0.27 mmol, 2 equivalents) were added and the mixture was stirred at RT overnight. Another 22 mg equivalent of TBTU (0.07 mmol, 0.5 equivalent) and 12 mg of 1,2-diamino-2-methylpropane (0.13 mmol, 1 equivalent) were added and the reaction was stirred at RT for 2 h. Water was added and the reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate. The mixture was filtered and concentrated and the resulting crude product was purified by thick layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution: 10: 0.5). This gave 31 mg of the title compound (55% of theory; purity 98%).

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 407.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6 H), 1.52 (br.s, 2 H), 3.15-3.23 (m, 2 H), 5.32 (s, 2 H), 7.19-7.32 (m, 3 H), 7.55-7.66 (m, 1 H), 7.75 (br.s, 1 H), 8.69-8.76 (m, 1 H), [Other signals are hidden under the solvent peak] .

Example 141: N- (3-amino-2,3-dimethylbut-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2- a] -Pyridine-3-carboxamide

75 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 3A, 0.24 mmol, 1 equivalent), 116 mg of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU, 0.31 mmol, 1.3 equivalents) and 152 mg of N, N-diisopropylethylamine (0.21 ml, 1.18 mmol, 5 equivalents) were dissolved in 1.6 ml of DMF. After 10 min at RT, 111 mg of , 3-dimethylbutane-2,3-diamine dihydrochloride (0.6 mmol, 2.5 eq.) And the mixture was stirred at RT overnight. The product was then purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The resulting product was dissolved in ethyl acetate and a saturated aqueous solution of sodium bicarbonate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 20 mg (20% of theory; 99% purity) of the title compound.

LC-MS (Method 7): R _t = 0.57min

MS (ES +): m / z = 417.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.13 (s, 6 H), 1.42 (s, 6 H), 2.58 (s, 3 H), 5.30 (s, 2 H), 6.93 (t, 1 H), 7.02 (d, 1 H), 7.23 (t, 2 H), 7.53-7.65 (m, 1 H), 7.92 (s, 1 H), 8.89 (d, 1 H).

The examples shown in Table 12 are similar to Example 141 with a suitable carboxylic acid (Examples 3A, 16A, and 21A) and a suitable amine (prepared as above or commercially available (1.05-2.5 equivalents)) and N, N-diisopropyl Ethylamine (3-6 equivalents) was prepared by reaction under the reaction conditions described in General Procedure 3.

Exemplary subsequent treatment of the reaction mixture: adding water to the reaction solution and stirring the formed precipitate for another 0.5-1.0 h, filtering, washing with water and drying under high vacuum overnight. another One option is to further purify the precipitate or crude reaction mixture directly by preparative HPLC (RPIR column, mobile phase: acetonitrile / water gradient with 0.1% TFA) and dry under high vacuum overnight. If appropriate, the product fractions are treated in ethyl acetate or dichloromethane and washed twice with saturated aqueous sodium bicarbonate. The aqueous phase is extracted twice with ethyl acetate or dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated.

¹⁾ An additional chromatographic separation: column: Sunfire C18, 5μm, 250 x 20mm, mobile phase: 89% methanol, 11% 1% TFA aqueous solution, flow rate: 25ml / min; 25 ° C, detection: 210nm ].

Example 168 N- [2- (4-cyclopropylpiper -1-yl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide

118 mg of 8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (2-oxoethyl) imidazo [1,2-a] pyridine-3-carboxyfluorene Amine (Example 194A, 0.16 mmol, 1 equivalent) was suspended in 0.8 ml of anhydrous dichloroethane, and 23 mg of 1-cyclopropylpiper (0.18 mmol, 1.1 equivalents) and the mixture was stirred at RT for 3 h. 52 mg of sodium triacetoxyborohydride (0.25 mmol, 1.5 equivalents) were then added, and the mixture was stirred at RT overnight. A 1 N aqueous sodium hydroxide solution was then added and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in methanol and purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 33.5 mg (43% of theory) of the title compound.

LC-MS (Method 7): R _t = 0.60min

MS (ES +): m / z = 470.2 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.22-0.30 (m, 2 H), 0.34-0.43 (m, 2 H), 1.53-1.62 (m, 1 H), 2.30-2.44 (m, 3 H), 3.37-3.46 (m, 2 H), 5.30 (s, 2 H), 6.93 (t, 1 H), 7.01 (d, 1 H), 7.23 (t, 2 H), 7.55-7.64 ( m, 1 H), 7.70 (t, 1 H), 8.67 (d, 1 H), [the other signal is hidden under the solvent peak].

The examples shown in Table 13 are similar to Example 168 prepared from aldehydes from Examples 194A, 195A, and 196A.

¹⁾ Secondary mirror isomers formed in the separation reaction on the palm phase (partial racemization under these conditions) [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C / 40 ° C, detection: 210 / 220nm].

Example 172 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N-[(2S) -piperidin-2-ylmethyl] imidazo [1,2-a] Pyridin-3-carboxamide

At RT, 53 mg (0.25 mmol, 1.1 equivalents) of (2S) -2- (aminomethyl) piperidine-1-carboxylic acid third butyl ester was added to 75 mg of 8-[(2,6-difluoro Benzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 21A, 0.23 mmol, 1 equivalent), 90 mg of O- (7-azabenzene Benzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU, 0.24 mmol, 1.05 eq) and 88 mg of N, N-diisopropylethylamine (0.12 ml, 0.68 mmol, 3 eq) in 1.4 ml of a DMF solution, and the mixture was stirred at RT overnight. After the reaction was completed, the mixture was purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The resulting product was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 66 mg (64% of theory; 95% purity) of the title compound.

LC-MS (Method 2): R _t = 0.65min

MS (ES +): m / z = 429.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.99-1.14 (m, 1 H), 1.21-1.36 (m, 2 H), 1.45-1.54 (m, 1 H), 1.59-1.66 (m, 1 H), 1.70-1.7 (m, 1 H), 2.31 (s, 3 H), 2.60-2.69 (m, 1 H), 2.92-2.98 (m, 1 H), 3.16-3.29 (m, 2 H ), 5.28 (s, 2 H), 6.91 (s, 1 H), 7.24 (t, 2 H), 7.55-7.64 (m, 1 H), 7.74 (t, 1 H), 8.46 (s, 1 H ), [Another signal is hidden under the solvent peak].

Example 173 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N-[(2R) -piperidin-2-ylmethyl] imidazo [1,2-a] Pyridin-3-carboxamide

56 mg of (2R) -2-{[({8-[(2,6-difluorobenzyl) oxy] -2,6- Dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] methyl} piperidine-1-carboxylic acid tert-butyl trifluoroacetate (0.09 mmol) was first placed in 2M hydrochloric acid In diethyl ether solution, and the mixture was stirred at RT for 5 h. The resulting precipitate was filtered and washed with ether, dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 30 mg (78% of theory; 95% purity) of the title compound.

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 429.3 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.99-1.14 (m, 1 H), 1.21-1.36 (m, 2 H), 1.45-1.54 (m, 1 H), 1.59-1.66 (m, 1 H), 1.71-1.77 (m, 1 H), 2.31 (s, 3 H), 2.60-2.69 (m, 1 H), 2.92-2.98 (m, 1 H), 3.16-3.29 (m, 2 H ), 5.28 (s, 2 H), 6.90 (s, 1 H), 7.24 (t, 2 H), 7.55-7.64 (m, 1 H), 7.74 (t, 1 H), 8.46 (s, 1 H ), [Another signal is hidden under the solvent peak].

Example 174 Enantiomer-N-[(3S) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a ] Pyridine-3-carboxamide (diastereomer A)

44.1 mg of N-[(3S) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2- a] Pyridin-3-carboxamide (Example 120) was separated into diastereomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isomeric Hexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: Diastereomer A: 19.7 mg (100% ee)

Diastereomer A: R _t = 8.90min [Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 25 ° C, detection: 230nm].

Example 175 Enantiomer-N-[(3S) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a ] Pyridine-3-carboxamide (diastereomer B)

44.1 mg of racemic-N-[(3S) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide (Example 120) was separated into diastereomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50 % Isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield Diastereomer B: 2.3 mg (> 90% ee)

Diastereomer A: R _t = 12.68min [Daicel Chiralpak AD-H, 5μm, 250 x 20mm, mobile phase: mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 25 ° C, detection: 230nm].

Example 176 Enantiomer-N-[(3R) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a ] Pyridine-3-carboxamide (diastereomer A)

90 mg of racemic-{(2R) -3-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3 -Yl} carbonyl) amino] but-2-yl} carbamic acid benzyl ester (Example 121) was separated into diastereomers on the palm phase [column: Daicel Chiralpak OD-H, 5 μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: Diastereomer A: 29.6 mg (100% ee)

Diastereomer A: R _t = 5.94min [Daicel Chiralpak OD-H, 5μm, 250 x 20mm, mobile phase: mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 25 ° C, detection: 230nm].

Example 177 Enantiomer-N-[(3R) -3-aminobut-2-yl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a ] Pyridine-3-carboxamide (diastereomer B)

90 mg of racemic-{(2R) -3-[({8-[(2,6-difluorobenzyl) oxy] -2-methyl Benzyl imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] but-2-yl} carbamic acid benzyl ester (Example 121) was separated on the palm phase into diastereomers Column: Daicel Chiralpak OD-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: Diastereomer B: 4.9 mg (88% ee)

Diastereomer B: R _t = 9.79min [Daicel Chiralpak OD-H, 5μm, 250 x 20mm, mobile phase: mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 25 ° C, detection: 230nm]

Example 178 Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] Pyridine-3-carboxamide (mirror isomer A)

113 mg of racemic-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1, 2-a] Pyridine-3-carboxamide (Example 46) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: mirror isomer A: 18.5 mg (89% ee)

Mirror isomer A: R _t = 7.89min [Daicel Chiralpak OD-H, 5μm, 250 x 4.6mm, mobile phase: mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ° C, detection: 220nm].

Example 179 Enantio-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] Pyridine-3-carboxamide (mirror isomer B)

113 mg of racemic-N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8- (cyclohexylmethoxy) -2-methylimidazo [1, 2-a] Pyridine-3-carboxamide (Example 46) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: mirror isomer B: 28 mg (97% ee)

Mirror isomer B: R _t = 12.84min [Daicel Chiralpak OD-H, 5μm, 250 x 4.6mm, mobile phase: mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ° C, detection: 220nm].

Example 180 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholinolin-4-yl) propyl] imidazo [1,2-a ] -Pyridine-3-carboxamide (Mirror Isomer A)

120 mg of racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholin-4-yl) propyl] imidazo [1 , 2-a] pyridine-3-carboxamide (Example 132) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane , 50% isopropanol, 0.2% diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer A: 45 mg (100% ee)

Mirror isomer A: R _t = 8.99min [Daicel Chiralpak AD-H, 5 μm, 250 x 4.6mm, mobile phase: mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ° C, detection: 220nm].

Example 181 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholinolin-4-yl) propyl] imidazo [1,2-a ] -Pyridine-3-carboxamide (Mirror Isomer B)

120 mg of racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholin-4-yl) propyl] imidazo [1 , 2-a] pyridine-3-carboxamide (Example 132) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane , 50% isopropanol, 0.2% diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer B: 47 mg (97% ee)

Mirror isomer B: R _t = 11.00min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ° C, detection: 220nm].

Example 182 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholinolin-4-yl) -1-phenylethyl] imidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

128 mg of racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholinolin-4-yl) -1-phenylethyl ] i imidazo- [1,2-a] pyridine-3-carboxamide (Example 134) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, Mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: mirror isomer A: 27 mg (100% ee)

Mirror isomer A: R _t = 8.96min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ℃, detection: 220nm].

Example 183 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholinolin-4-yl) -1-phenylethyl] imidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

128 mg of racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- [2- (morpholinolin-4-yl) -1-phenylethyl ] Imidazolo- [1,2-a] pyridine-3-carboxamide (Example 134) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, moving Phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Yield: mirror isomer B: 23 mg (100% ee)

Mirror isomer B: R _t = 13.66min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ℃, detection: 220nm].

Example 184 Enantiomer-N- (3-azabicyclo [4.1.0] hept-1-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirromeric isomer A)

111 mg of Example 125 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethyl Amine, flow rate: 20 ml / min; 40 ° C, detection: 210 nm].

Yield: mirror isomer A: 32 mg (99% ee)

Mirror isomer A: R _t = 8.04min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ℃, detection: 220nm].

Example 185 Enantiomer-N- (3-azabicyclo [4.1.0] hept-1-yl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

111 mg of Example 125 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethyl Amine, flow rate: 20 ml / min; 40 ° C, detection: 210 nm].

Yield: mirror isomer B: 31 mg (100% ee)

Mirror isomer B: R _t = 11.10min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol, 0.2% diethylamine, flow rate: 1ml / min; 40 ℃, detection: 220nm].

Example 186 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- [2- (morpholin-4-yl) propyl] imidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

63 mg of Example 138 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethyl Amine, flow rate: 20 ml / min; 40 ° C, detection: 210 nm].

Yield: mirror isomer A: 21 mg (96% ee)

Mirror isomer A: R _t = 8.73min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 1ml / min 40 ° C, detection: 220nm].

Example 187 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- [2- (morpholin-4-yl) propyl] imidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

63 mg of Example 138 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol, 0.2% diethyl Amine, flow rate: 20 ml / min; 40 ° C, detection: 210 nm].

Yield: mirror isomer B: 25 mg (100% ee)

Mirror isomer B: R _t = 9.70min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 1ml / min 40 ° C, detection: 220nm].

Example 188 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -N- [2- (dimethylamino) -3-methylbutyl] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirromeric isomer A)

130 mg of Example 142 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, Flow rate: 20ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer A: 50mg (99% ee)

Mirror isomer A: R _t = 8.31min [column: Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 1ml / min; 40 ° C, detection: 220nm].

Example 189 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -N- [2- (dimethylamino) -3-methylbutyl] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

130 mg of Example 142 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, Flow rate: 20ml / min; 40 ° C, detection: 210nm].

Yield: mirror isomer B: 52 mg (96% ee)

Mirror isomer B: R _t = 9.66min [column: Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 1ml / min; 40 ° C, detection: 220nm].

Example 190 Enantiomer-6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (piperidin-2-ylmethyl) imidazo [1,2-a] Pyridine-3-carboxamide (mirror isomer A)

130 mg of Example 118 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethyl Amine, flow rate: 15 ml / min; 40 ° C, detection: 220 nm].

Yield: mirror isomer A: 65mg (99% ee)

Mirror isomer A: R _t = 10.35min [column: Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 220nm].

Example 191 Enantiomer-6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (piperidin-2-ylmethyl) imidazo [1,2-a] Pyridine-3-carboxamide (mirror isomer B)

130 mg of Example 118 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethyl Amine, flow rate: 15 ml / min; 40 ° C, detection: 220 nm].

Yield: mirror isomer B: 66 mg (98% ee)

Mirror isomer B: R _t = 11.67min [column: Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 220nm].

Example 192 Enantiomer-N- (2-amino-4,4,4-trifluorobutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

166 mg of Example 147 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethyl Amine, flow rate: 12 ml / min; 25 ° C, detection: 230 nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized. The product was repurified by thick layer chromatography (mobile phase: dichloromethane / methanol 10: 1).

Yield Mirror Isomer A: 23 mg (99% ee)

Mirror image isomer A: R _t = 5.63min [column: Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 220nm].

Example 193 Enantiomer-N- (2-amino-4,4,4-trifluorobutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

166 mg of Example 147 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropyl Alcohol + 0.2% diethylamine, flow rate: 12ml / min; 25 ° C, detection: 230nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized. The product was repurified by thick layer chromatography (mobile phase: dichloromethane / methanol 10: 1).

Yield: mirror isomer B: 22 mg (99% ee)

Mirror isomer B: R _t = 6.13min [column: Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 220nm].

Example 194 Enantiomer-N- (2-amino-2-methylbutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

190 mg of Example 157 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 35 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized.

Yield: mirror isomer A: 54 mg (98% ee)

Mirror isomer A: R _t = 8.39min [column: Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 35 ° C, detection: 250nm].

Specific rotation [α] (436nm, 19.8 ℃) =-3.2 ° (c = 0.0044g / ml, acetonitrile)

Example 195 Enantiomer-N- (2-amino-2-methylbutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

190 mg of Example 157 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate : 15ml / min; 35 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized.

Yield: mirror isomer B: 71 mg (90% ee)

Mirror isomer B: R _t = 9.04min [column: Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 35 ° C, detection: 250nm].

Example 196 Enantiomer-N- (2-amino-3-methoxy-2-methylpropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methyl Imidazolo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

218 mg of Example 159 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized.

Yield: mirror isomer A: 136 mg (99% ee)

Mirror isomer A: R _t = 7.68min [column: Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 270nm].

Example 197 Enantiomer-N- (2-amino-3-methoxy-2-methylpropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methyl Imidazolo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

218 mg of Example 159 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm]. Collect produce on dry ice The fractions were combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized.

Yield: mirror isomer B: 60 mg (98% ee)

Mirror isomer B: R _t = 10.17min [column: Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 40 ° C, detection: 270nm].

Example 198 Enantio-N- (2-amino-3-methoxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

200 mg of Example 166 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, Flow rate: 12ml / min; 45 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized.

Yield: mirror isomer A: 112 mg (99% ee)

Mirror image isomer A: R _t = 7.31min [column: Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, flow rate: 1.0ml / min; 45 ° C, detection: 235nm].

Example 199 Enantiomer-N- (2-amino-3-methoxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimide Zolo [1,2-a] pyridine-3-carboxamidine (mirror isomer B)

200 mg of Example 166 was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, Flow rate: 12ml / min; 45 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The mixture was frozen and lyophilized.

Yield: mirror isomer B: 50 mg (98% ee)

Mirror isomer B: R _t = 10.00min [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 4.6 mm, mobile phase: 25% isohexane, 75% ethanol + 0.2% diethylamine, flow rate: 1.0 ml / min; 45 ° C, detection: 235nm].

Example 200 Enantio-N-[(2S) -amino-2-methylbutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1, 2-a] pyridine-3-carboxamide (mirromeric isomer A)

With slow heating, 3.55 g (6.45 mmol) of the enantiomer- {1-[({8-[(2,6- 二 Fluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl Ester (Mirror Isomer A) Example 276A was dissolved in 70 ml of ethanol and 226 mg of activated carbon was added to palladium (II) hydroxide (20%) under argon. The reaction mixture was hydrogenated at RT and atmospheric pressure for 2 h. The reaction mixture was filtered through celite, the filter cake was thoroughly washed with ethanol and the filtrate was concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 10 / 0.5). This gave 2.27 g of the target compound (85% of theory; 99% purity).

LC-MS (Method 2): R _t = 0.62min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.97 (s, 3H), 1.31-1.39 (m, 2H), 1.43 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H, overlap with DMSO signal), 3.14-3.27 (m, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.19-7.27 (m, 2H), 7.54-7.64 (m, 2H), 8.49 (s, 1H).

Specific rotation [α] (365nm, 20.0 ℃) =-6.6 ° (c = 0.0044g / ml, acetonitrile)

Single crystal X-ray structure analysis confirmed that this mirror isomer is of S configuration.

Example 201 Enantiomer-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer B)

With slow temperature rise, 2.10 g (3.66 mmol) of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1 , 2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester (mirror isomer B) Add anger 257 mg of activated carbon was charged with palladium (II) hydroxide (20%). The reaction mixture was hydrogenated at RT and atmospheric pressure for 2 h. The reaction mixture was filtered through celite, the filter cake was thoroughly washed with ethanol and the filtrate was concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 10 / 0.5). This gave 1.26 g of the target compound (82% of theory; 99% purity).

LC-MS (Method 2): R _t = 0.66min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.98 (s, 3H), 1.31-1.39 (m, 2H), 1.49 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H, overlap with DMSO signal), 3.14-3.27 (m, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.19-7.27 (m, 2H), 7.54-7.64 (m, 2H), 8.49 (s, 1H).

Specific rotation [α] (365nm, 20.1 ℃) = + 4.4 ° (c = 0.0044g / ml, acetonitrile)

Example 202 Racemic-N- (2-amino-2,4-dimethylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide

150 mg (0.47 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A was first placed in DMF ( 1.7 ml), and 159 mg (0.50 mmol) of TBTU and 0.16 ml (1.41 mmol) of 4-methylmorpholine were added. 68 mg (0.52 mmol) of racemic-2,4-dimethylpentane-1,2-diamine were then added and the reaction mixture was stirred at RT overnight. Another 6.1 mg (0.04 mmol) of racemic-2,4-dimethylpentan-1,2-diamine was added and the reaction was mixed The mixture was stirred at RT for 20 min. The mixture was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was treated in dichloromethane and a few drops of methanol and washed twice with saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted three times with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 126 mg (61% of theory, 97% purity) of the target compound.

LC-MS (Method 2): R _t = 0.70min

MS (ESI +): m / z = 431 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.89 (d, 3H), 0.95 (d, 3H), 1.02 (s, 3H), 1.20-1.33 (m, 2H), 1.42 (br.s, 2H), 1.74-1.85 (m, 1H), 2.56 (s, 3H), 3.14-3.27 (m, 2H), 5.30 (s, 2H), 6.94 (t, 1H), 7.01 (d, 1H), 7.19 -7.29 (m, 2H), 7.54-7.63 (m, 1H), 7.64-7.71 (m, 1H), 8.64 (d, 1H).

Example 203 Enantiomer-N- (2-amino-2,4-dimethylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer A)

122 mg of Example 202 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer A: Yield: 28 mg (100% ee)

R _t = 8.71min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 204 Enantiomer-N- (2-amino-2,4-dimethylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer B)

122 mg of Example 202 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer B: Yield: 68 mg (92% ee)

R _t = 9.79min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 205 Racemic-N- (2-amino-3-isopropoxypropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2- a] pyridine-3-carboxamide

Add 125 mg (0.33 mmol) of HATU and 0.16 ml (0.90 mmol) of N, N-diisopropylethylamine to 95 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy ] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A in a DMF solution (1.9 ml), and the mixture was stirred at RT for 20 min. At -20 ° C, 0.31 ml (1.8 mmol) of N, N-diisopropylethylamine and 145 mg (0.54 mmol, 76% purity) of racemic-3- A solution of isopropyloxypropane-1,2-diamine dihydrochloride Example 224A in DMF (0.5 ml) was slowly added dropwise to the reaction mixture. The mixture was stirred at RT overnight. The mixture was then diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and then repurified by thick layer chromatography (dichloromethane / methanol: 10: 1). This gave 15 mg (12% of theory) of the target compound.

LC-MS (Method 2): R _t = 0.68min.

MS (ESI +): m / z = 433 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.10 (d, 6H), 1.24 (s, 2H), 2.57 (s, 3H; overlap with DMSO signal), 3.00-3.08 (m, 1H), 3.28 -3.48 (m, 4H), 3.51-3.59 (m, 1H), 5.30 (s, 2H), 6.92 (t, 1H), 7.00 (d, 1H), 7.24 (t, 2H), 7.53-7.63 (m , 1H), 7.70 (t, 1H), 8.64 (d, 1H).

Example 206 Racemic-N- (2-amino-3-isopropoxypropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1 , 2-a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 205. With 11.2 mg (0.03 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A and 15.0 mg (0.05 mmol, 76% purity) of racemic-3-isopropoxypropane-1,2-diamine dihydrochloride Example 224A was used as starting material to obtain 1.6 mg (9.5% of theory) Target compound.

LC-MS (Method 2): R _t = 0.65min

MS (ESI +): m / z = 447 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.14 (d, 6H), 1.25 (s, 2H), 2.32 (s, 3H), 2.54 (s, 3H; overlap with DMSO signal), 3.35-3.42 (m, 1H), 3.44-3.66 (m, 5H), 5.31 (s, 2H), 6.94 (s, 1H), 7.24 (t, 2H), 7.56-7.66 (m, 1H), 7.80 (t, 1H ), 8.53 (s, 1H).

Example 207 Racemic-N- (2-amino-3,3,3-trifluoropropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 141. With 400 mg (1.26 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A and 278 mg (1.38 mmol ) Racemic-1- (trifluoromethyl) ethylidene-1,2-diamine dihydrochloride was used as a starting material to obtain 340 mg (63% of theory) of the target compound.

LC-MS (Method 7): R _t = 0.70min

MS (ESI +): m / z = 429 (M + H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.55 (s, 3H; overlap with DMSO signal), 3.49-3.62 (m, 1H), 3.67-3.77 (m, 1H), 3.89-4.10 (m, 1H), 5.31 (s, 2H), 6.99 (t, 1H), 7.07 (d, 1H), 7.19-7.29 (m, 2H), 7.54-7.65 (m, 1H), 7.96 (t, 1H), 8.71 (d, 1H).

Example 208 Enantiomer-N- (2-amino-3,3,3-trifluoropropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

464 mg of Example 207 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm].

Mirror isomer A: Yield: 120 mg (100% ee)

R _t = 8.87min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection : 220nm].

Example 209 Enantiomer-N- (2-amino-3,3,3-trifluoropropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

464 mg of Example 207 was separated into mirror isomers on the palm phase by preparative separation [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm].

Mirror isomer B: Yield: 122 mg (92.6% ee)

R _t = 10.05min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection : 220nm].

Example 210 Enantiomer-N- (1-amino-3-methoxyprop-2-yl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide trifluoroacetate (mirromeric isomer B)

Under argon, 100 mg (0.18 mmol) of the enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1, 2-a] pyridin-3-yl} carbonyl) amino] -3-methoxypropyl} carbamic acid benzyl ester, prepared according to representative operation process 3 using examples 21A and 248A) First put in ethanol (1.3 ml), and added 19.2 mg (0.02 mmol, 10%) of palladium on activated carbon and 0.37 ml (3.62 mmol) of cyclohexene. The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to RT, filtered through a Millipore ^® filter cake was washed with ethanol and the filtrate was concentrated. The residue was purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated, then treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 24 mg (22% of theory, 90% purity) of the title compound.

LC-MS (Method 7): R _t = 0.59min

MS (ESI +): m / z = 419 (M-TFA + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.36 (s, 3H), 2.53 (s, 3H; overlap with DMSO signal), 2.93-3.04 (m, 1H), 3.06-3.17 (m, 1H) , 3.32 (s, 3H), 3.47-3.54 (m, 2H), 4.37-4.48 (m, 1H), 5.34 (s, 2H), 7.10-7.19 (m, 1H), 7.21-7.39 (m, 2H) , 7.61 (quintet, 1H), 7.83-8.00 (m, 2H), 8.46 (s, 1H).

Example 211 Enantiomer-N- (2-amino-3-methylbutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

124 mg (0.23 mmol) of enantiomer- {1-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] Pyridin-3-yl} carbonyl) amino] -3-methylbut-2-yl} carbamic acid third butyl ester Example 228A was first put into 1.16 ml (2.31 mmol) of 2N hydrogen chloride / ether, and the mixture was placed in Stir at RT for 3.5h. The reaction solution was then concentrated. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the residue. After phase separation, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 89 mg (87% of theory, 99% purity) of the title compound.

LC-MS (Method 2): R _t = 0.73min

MS (ESI +): m / z = 437 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88 (d, 3H), 0.92 (d, 3H), 1.57-1.68 (m, 1H), 1.86-2.24 (br.s, 2H), 2.53 ( s, 3H; overlap with DMSO signal), 2.63-2.70 (m, 1H), 3.05-3.14 (m, 1H), 3.39-3.46 (m, 1H), 5.34 (s, 2H), 7.19 (d, 1H) , 7.26 (t, 2H), 7.61 (five-fold peak, 1H), 7.72-7.88 (br.s, 1H), 8.78 (d, 1H).

Example 212 Enantiomer-N- (2-amino-3-methylbutyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

The title compound was prepared and purified similarly to Example 211 (using dichloromethane as a follow-up treatment). With 122 mg (0.23 mmol) of enantiomer- {1-[({6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] Pyridin-3-yl} carbonyl) amino] -3-methylbut-2-yl} carbamic acid third butyl ester (mirromeric isomer B) Example 229A was used as starting material to obtain 81 mg (81% of theoretical value , Purity 99%) of the title compound.

LC-MS (Method 2): R _t = 0.73min

MS (ESI +): m / z = 437 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88 (d, 3H), 0.91 (d, 1H), 1.45-1.78 (m, 3H), 2.52 (s, 3H; overlap with DMSO signal), 2.61 -2.69 (m, 1H), 3.04-3.13 (m, 1H), 3.38-3.45 (m, 1H), 5.34 (s, 2H), 7.19 (d, 1H), 7.26 (t, 2H), 7.60 (Five Heavy peak, 1H), 7.71-7.88 (br.s, 1H), 8.78 (d, 1H).

Example 213 Racemic-N- (2-amino-3-methoxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide

180 mg (0.57 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A, 237 mg (0.62 mmol) HATU) and 0.30 ml (1.70 mmol) of N, N-diisopropylethylamine were first placed in 3.6 ml of DMF, and the mixture was stirred at RT for 20 min. 74 mg (0.62 mmol) of racemic-3-methoxy-2-methylpropan-1,2-diamine were then added and the reaction mixture was stirred at RT overnight. The reaction solution was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 136 mg (56% of theory, 98% purity) of the title compound.

LC-MS (Method 2): R _t = 0.56min

MS (ESI +): m / z = 419 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.00 (s, 3H), 1.53 (br.s, 2H), 2.56 (s, 3H; overlap with DMSO signal), 3.13-3.19 (m, 2H) , 3.24-3.32 (m, 5H; overlapping with the solvent signal), 5.30 (s, 2H), 6.94 (t, 1H), 7.02 (d, 1H), 7.19-7.29 (m, 2H), 7.59 (five-fold peak) , 2H), 8.69 (d, 1H).

Example 214 Enantio-N- (2-amino-3-methoxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer A)

130 mg of Example 213 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Phenomenex Amylose II, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% two Ethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Mirror isomer A: Yield: 32.4 mg (100% ee)

R _t = 5.89min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 215 Enantio-N- (2-amino-3-methoxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer B)

130 mg of Example 213 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Phenomenex Amylose II, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% two Ethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Mirror isomer B: Yield: 79.5 mg (100% ee)

R _t = 8.01min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 216 N-[(3-Aminooxo-3-yl) methyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 205. With 45 mg (0.14 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A and 95 mg (0.41 mmol, 75% purity) 3- (aminomethyl) oxo-3-amine dihydrochloride Example 226A was the starting material. After purification [column: XBridge C18, 5μm, 150 x 19mm, mobile phase: 32% water, 60% methanol + 8% 1% ammonia water, flow rate: 25ml / min; 25 ° C, detection: 210nm], This gave 21 mg (37% of theory, 100% purity) of the target compound.

LC-MS (Method 2): R _t = 0.63min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.30 (s, 3H), 3.52-3.62 (m, 2H), 4.29 (d, 2H), 4.43 (d, 2H), 5.29 (s, 2H) , 6.92 (s, 1H), 7.19-7.28 (m, 2H), 7.54-7.65 (m, 1H), 7.88-7.98 (m, 1H), 8.44 (s, 1H), [Additional signals are under the DMSO peak ].

Example 217 Racemic-N- (2-amino-3-isopropoxypropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimid Zolo [1,2-a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 205. 11.9 mg (0.03 mmol) of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 16A And 15.0 mg (0.06 mmol, 76% purity) of racemic-3-isopropoxypropane-1,2-diamine dihydrochloride Example 224A as the starting material to obtain 1.9 mg (11% of 90% purity) of the target compound.

LC-MS (Method 2): R _t = 0.76min

MS (ESI +): m / z = 467 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.14 (d, 6H), 1.23-1.28 (m, 2H), 2.55 (s, 3H; overlap with DMSO signal), 3.41-3.56 (m, 4H) , 3.58-3.65 (m, 1H), 5.34 (s, 2H), 7.19-7.28 (m, 3H), 7.56-7.66 (m, 1H), 8.80 (d, 1H).

Example 218 Racemic-N- (2-amino-2,4-dimethylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 202. 150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A and 65 mg (0.50 mmol) of racemic-2,4-dimethylpentane-1,2-diamine as a starting material, 155 mg (73% of the theoretical value, 95% purity) of the target compound were obtained.

LC-MS (Method 2): R _t = 0.66min

MS (ESI +): m / z = 445 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.89-0.96 (m, 6H), 1.02 (s, 3H), 1.21-1.34 (m, 2H), 1.67 (br.s, 2H), 1.74- 1.85 (m, 1H), 2.31 (s, 3H), 2.53 (br.s, 3H; overlap with DMSO signal), 3.14-3.27 (m, 2H), 5.28 (s, 2H), 6.92 (s, 1H) , 7.20-7.28 (m, 2H), 7.55-7.68 (m, 2H), 8.48 (s, 1H).

Example 219 Enantiomer-N- (2-amino-2,4-dimethylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer A)

155 mg of Example 218 was separated into mirror isomers by preparative separation on the counter palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm].

Mirror isomer A: Yield: 37 mg (100% ee)

R _t = 11.40min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 220 Enantiomer-N- (2-amino-2,4-dimethylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer B)

155 mg of Example 218 was separated into mirror isomers by preparative separation on the counter palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20 mm, mobile phase: 70% isohexane, 30% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 40 ° C, detection: 210nm].

Mirror isomer B: Yield: 79 mg (93% ee)

R _t = 12.56min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 70% isohexane, 30% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Specific rotation [α] (365nm, 19.6 ℃) = + 17.7 ° (c = 0.005g / ml, acetonitrile)

Example 221 N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine -3-carboxamide hydrochloride

200 mg (0.50 mmol) of N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamidine Example 74 was first put into 4 ml of diethyl ether, 0.26 ml (0.52 mmol) of 2N hydrochloric acid in diethyl ether was added, and the reaction mixture was stirred at RT for 30 min. The mixture was then concentrated and the residue was lyophilized. This gave 217 mg (98.5% of theory, 99% purity) of the target compound.

LC-MS (Method 7): R _t = 0.57min

MS (ESI +): m / z = 403 (M-HCl + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.24 (s, 6H), 2.32 (s, 3H), 2.55 (br.s, 3H; overlap with DMSO signal), 3.42 (d, 2H), 5.29 (s, 2H), 6.95 (s, 1H), 7.15 (br.s, 2H), 7.21-7.28 (m, 2H), 7.55-7.64 (m, 1H), 7.96-8.03 (m, 1H), 8.47 (m, 1H).

Example 222 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -N- {1- (3,4-difluorophenyl) -2-[(2,2,2-trifluoroethyl ) Amine] ethyl} -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

100 mg (0.21 mmol) of N- [2-amino-1- (3,4-difluorophenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2- Methylimidazo [1,2-a] pyridine-3-carboxamide Example 13 was first placed in 2 ml of DMF, and 35 μl (0.21 mmol) of trichloromethanesulfonic acid 2,2,2-trifluoroethyl Ester, 59 mg (0.42 mmol) of potassium carbonate and 3.5 mg (0.02 mmol) of potassium iodide and the reaction mixture was stirred at RT overnight. 10 ml of water was added and the reaction solution was extracted twice with 30 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water and with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative RP-HPLC (acetonitrile / water with 0.5% concentrated formic acid gradient). The product fractions were concentrated to almost dryness, 1 ml of tert-butanol was added and the mixture was lyophilized overnight. This gave 18 mg (14% of theory, 91% purity) of the target compound.

LC-MS (Method 2): R _t = 1.05min

MS (ESI +): m / z = 555 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.57 (s, 3H), 2.89-3.08 (m, 2H), 5.09-5.18 (m, 1H), 5.30 (s, 2H), 6.91 (t, 1H), 7.02 (d, 1H), 7.18-7.33 (m, 3H), 7.36-7.46 (m, 1H), 7.47-7.56 (m, 1H), 7.57-7.64 (m, 1H), 8.17 (d, 1H), 8.53 (d, 1H), [the additional signal is hidden under the solvent peak].

Example 223 Enantiomer-N- (2-amino-3-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer A)

88 mg (0.17 mmol) of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine 3--3-yl} carbonyl) amino] -3-methylbut-2-yl} carbamic acid third butyl ester (mirromeric isomer A) Example 231A in 0.85 ml of 2N hydrochloric acid / ether and stirred at RT for 4 h . The reaction mixture was concentrated and the residue was dissolved in dichloromethane and a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 64 mg (88% of theory, 98% purity) of the target compound.

LC-MS (Method 7): R _t = 0.62min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88 (d, 3H), 0.92 (d, 3H), 1.39-1.56 (br.s, 2H), 1.56-1.65 (m, 1H), 2.31 ( s, 3H), 2.60-2.66 (m, 1H), 3.02-3.11 (m, 1H), 3.38-3.45 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.28 ( m, 2H), 7.55-7.64 (m, 1H), 7.70 (t, 1H), 8.49 (s, 1H), [additional signal under DMSO peak].

Example 224 Enantiomer-N- (2-amino-3-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer B)

The title compound was prepared and purified similarly to Example 223. With 92 mg (0.18 mmol) of enantiomer-1-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-yl} carbonyl) amino] -3-methylbut-2-yl} carbamic acid third butyl ester (mirror isomer B) Example 232A was used as starting material to obtain 67 mg (88% of theoretical value, purity 98%) of the target compound.

LC-MS (Method 7): R _t = 0.64min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.89 (d, 3H), 0.92 (d, 3H), 1.19-1.30 (br.s, 2H), 1.55-1.69 (m, 2H), 2.31 ( s, 3H), 2.60-2.68 (m, 1H), 3.02-3.11 (m, 1H), 3.39-3.46 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.28 ( m, 2H), 7.55-7.64 (m, 1H), 7.67-7.73 (m, 1H), 8.48 (s, 1H), [additional signal under DMSO peak].

Example 225 Racemic-N- (2-amino-2,4-dimethylpentyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide

Add 61 mg (0.47 mmol) of racemic-2,4-dimethylpentane-1,2-diamine to 150 mg (0.43 mmol) of 6-chloro-8-[(2,6-difluorobenzyl) ) Oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid example 16A, 143 mg (0.45 mmol) of TBTU and 0.19 ml (1.70 mmol) of 4-methylmorpholine DMF solution (1.5 ml) and the reaction mixture was stirred at RT overnight. The mixture was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 162 mg (79% of theory, 96% purity) of the target compound.

LC-MS (Method 7): R _t = 0.75min

MS (ESI +): m / z = 465 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.91 (d, 3H), 0.94 (d, 3H), 1.02 (s, 3H), 1.20-1.33 (m, 2H), 1.35-1.55 (br. s, 2H), 1.73-1.85 (m, 1H), 2.55 (s, 3H; overlap with DMSO signal), 3.21 (q, 2H), 5.35 (s, 2H), 7.20 (d, 1H), 7.22-7.29 (m, 2H), 7.57-7.65 (m, 1H), 7.67-7.80 (br.s, 1H), 8.76 (d, 1H).

Example 226 Enantiomer-N- (2-amino-2,4-dimethylpentyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

155 mg of Example 225 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 30 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 40ml / min; 25 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized. The product was then repurified by thick layer chromatography (mobile phase: dichloromethane / methanol: 20/1).

Mirror isomer A: Yield: 18 mg (100% ee)

R _t = 8.53min [Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 227 Enantiomer-N- (2-amino-2,4-dimethylpentyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

155 mg of Example 225 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 30 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 40ml / min; 25 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized. The product was then repurified by thick layer chromatography (mobile phase: dichloromethane / methanol: 20/1).

Mirror isomer B: Yield: 31 mg (88% ee)

R _t = 10.41min [Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 228 Enantiomer-N- (2-amino-3-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine -3-carboxamide (mirror isomer A)

The title compound was prepared and purified similarly to Example 230A. With 88 mg (0.18 mmol) of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3- Group} carbonyl) amino] -3-methylbut-2-yl} carbamic acid third butyl ester (mirror isomer A) Example 234A was used as starting material to obtain 64 mg (89% of theory, purity 98%) ) Of the target compound.

LC-MS (Method 7): R _t = 0.61min

MS (ESI +): m / z = 403 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.90 (d, 3H), 0.94 (d, 3H), 1.19-1.30 (br.s, 2H), 1.64-1.75 (m, 1H), 2.72- 2.78 (m, 1H), 3.12-3.21 (m, 1H), 3.41-3.49 (m, 1H), 5.30 (s, 2H), 6.94 (t, 1H), 7.01 (d, 1H), 7.20-7.28 ( m, 2H), 7.59 (five-fold peak, 1H), 7.74-7.79 (m, 1H), 8.67 (d, 1H), [additional signal under DMSO peak].

Example 229 Enantiomer-N- (2-amino-3-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine -3-carboxamide (mirror isomer B)

The title compound was prepared and purified similarly to Example 223. With 72 mg (0.14 mmol) of enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3- Group} carbonyl) amino] -3-methylbut-2-yl} carbamic acid third butyl ester (mirror isomer B) Example 235A was used as starting material to obtain 52 mg (88% of theory, purity 98%) ) Of the target compound.

LC-MS (Method 7): R _t = 0.63min

MS (ESI +): m / z = 403 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.88-0.97 (m, 6H), 1.19-1.29 (br.s, 2H), 1.64-1.76 (m, 1H), 2.73-2.80 (m, 1H ), 3.14-3.23 (m, 1H), 3.41-3.49 (m, 1H), 5.30 (s, 2H), 6.94 (t, 1H), 7.02 (d, 1H), 7.19-7.28 (m, 2H), 7.59 (five-fold peak, 1H), 7.73-7.82 (m, 1H), 8.67 (d, 1H), [additional signal under DMSO peak]

Example 230 Racemic-N- (2-amino-3,3,4,4-tetrafluorobutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [ 1,2-a] pyridine-3-carboxamide

400 mg (1.26 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A, 526 mg (1.38 mmol) HATU) and 1.1 ml (6.28 mmol) of N, N-diisopropylethylamine were stirred in DMF (8.0 ml) at RT for 20 min. Then 322 mg (1.38 mmol) of racemic-1- (1,1,2,2-tetrafluoroethyl) endeline-1,2-diamine dihydrochloride was added and the reaction mixture was stirred at RT Until overnight. The mixture was then purified directly by preparative RP-HPLC (acetonitrile / water with 0.05% concentrated formic acid). This gave 283 mg (49% of theory, 98% purity) of the target compound.

LC-MS (Method 2): R _t = 0.75min

MS (ESI +): m / z = 461 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.56 (s, 3H; overlap with DMSO signal), 3.37-3.47 (m, 1H), 3.52-3.67 (m, 1H), 3.67-3.76 (m, 1H), 5.31 (s, 2H), 6.68 (tt, 1H), 6.97 (t, 1H), 7.05 (d, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.83 (t, 1H), 8.71 (d, 1H).

Example 231 Enantiomer-N- (2-amino-3,3,4,4-tetrafluorobutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

240 mg of Example 230 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 25 ° C, detection: 230nm].

Mirror isomer A: Yield: 91.6 mg (100% ee)

R _t = 9.18min [Daicel Chiralcel OZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Mirror isomer A was purified by preparative RP-HPLC (acetonitrile / water with 0.05% concentrated formic acid). The impure product was purified again [column: Sunfire C18, 5 μm, 250 x 20 mm, mobile phase: 55% water, 45% acetonitrile, flow rate: 25 ml / min; 25 ° C., detection: 210 nm]. Thus, 48.5 mg (99% purity) of the target compound was obtained.

Example 232 Racemic-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide

77 mg (0.66 mmol) of racemic-2-methylpentane-1,2-diamine was added to 200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2, 6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid example 21A, 203 mg (0.63 mmol) of TBTU and 0.27 ml (2.41 mmol) of 4-methylmorpholine in DMF (2.1 ml ) Solution, and the reaction mixture was stirred at RT overnight. The mixture was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 199 mg (76% of theory, 99% purity) of the target compound.

LC-MS (Method 2): R _t = 0.67min

MS (ESI +): m / z = 431 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.99 (s, 3H), 1.22-1.42 (m, 4H), 1.43-1.67 (br.s, 2H), 2.31 ( s, 3H), 2.53 (s, 3H; overlap with DMSO signal), 3.14-3.26 (m, 2H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.55 -7.66 (m, 2H), 8.47 (s, 1H).

Example 233 Enantiomer-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer A)

195 mg of Example 232 was separated into the mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 60% isohexane, 40% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 25 ° C, detection: 220nm]. The product was then repurified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was dissolved in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated.

Mirror isomer A: Yield: 63 mg (99% ee)

R _t = 4.32min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Specific rotation [α] (365nm, 19.9 ℃) = + 31.8 ° (c = 0.005g / ml, acetonitrile)

Example 234 Enantiomer-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer B)

195 mg of Example 232 was separated into the mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AY-H, 5 μm, 250 x 20 mm, mobile phase: 60% isohexane, 40% ethanol + 0.2 % Diethylamine, flow rate: 20ml / min; 25 ° C, detection: 220nm]. The product was then repurified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was dissolved in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated.

Mirror isomer B: Yield: 64 mg (89% ee)

R _t = 5.09min [Daicel Chiralpak AY-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 235 Racemic-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- (1,2,3,4-tetrahydroquinolin-2-ylmethyl ) Imidazo [1,2-a] pyridine-3-carboxamide

182 mg (0.32 mmol) of racemic-2-{[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridin-3-yl} carbonyl) amino] methyl} -3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester Example 240A Put 5 ml of ether and 1.58 ml (3.16 mmol) 2N hydrochloric acid / ether and the mixture was stirred at RT overnight. Then 1 ml (2 mmol) of 2N hydrochloric acid / diethyl ether was added and stirring was continued at RT overnight. The reaction mixture was filtered and the filter cake was washed with ether. The solid was treated in dichloromethane and a very small amount of methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate. The mixture was filtered, concentrated and dried under high vacuum. This gave 140 mg (91% of theory, 98% purity) of the target compound.

LC-MS (Method 2): R _t = 1.01min

MS (ESI +): m / z = 477 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.55-1.67 (m, 1H), 1.86-1.96 (m, 1H), 2.31 (s, 3H), 2.69 (t, 2H), 3.36-3.50 ( m, 3H), 5.28 (s, 2H), 5.72 (s, 1H), 6.43 (t, 1H), 6.48 (d, 1H), 6.82-6.89 (m, 2H), 6.92 (s, 1H), 7.19 -7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.91 (t, 1H), 8.46 (s, 1H), [Other signals are hidden under the DMSO peak].

Example 236 Racemic-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy]- 2-methylimidazo [1,2-a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 225. 200 mg (0.57 mmol) of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 16A and 111 mg (0.62 mmol) of racemic-3,3,3-trifluoro-2-methylpropan-1,2-diamine hydrochloride Example 246A was used as starting material to obtain 211 mg (74% of the theoretical value, 95% purity) of the target compound.

LC-MS (Method 2): R _t = 0.98min

MS (ESI +): m / z = 477 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.23 (s, 3H), 2.55 (s, 3H: overlap with DMSO signal), 3.47-3.64 (m, 2H), 5.35 (s, 2H), 7.21 -7.30 (m, 3H), 7.56-7.67 (m, 1H), 7.92-8.01 (m, 1H), 8.76 (d, 1H).

Example 237 Enantiomer-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2 -Methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

204 mg of Example 236 was separated into a mirror by preparative separation on the opposite palm phase Image isomers [column: Daicel Chiralpak OZ-H, 5μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 17ml / min; 40 ° C, detection Measurement: 210nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer A: Yield: 50 mg (99% ee)

R _t = 9.71min [Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection : 220nm].

Example 238 Enantiomer-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2 -Methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

204 mg of Example 236 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak OZ-H, 5 μm, 250 x 20 mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 17ml / min; 40 ° C, detection: 210nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer B: Yield: 69 mg (91% ee)

R _t = 11.21min [Daicel Chiralpak OZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection : 220nm].

Example 239 Racemic-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6- Second Imidazo [1,2-a] pyridine-3-carboxamide

118 mg (0.66 mmol) of racemic-3,3,3-trifluoro-2-methylpropan-1,2-diamine hydrochloride Example 246A was added to 200 mg (0.60 mmol) of 8-[(2 , 6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A, 203 mg (0.63 mmol) of TBTU and 0.27 ml (2.41 mmol ) In a solution of 4-methylmorpholine in DMF (2.1 ml), and the reaction mixture was stirred at RT overnight. 50 mg (0.28 mmol) of racemic-3,3,3-trifluoro-2-methylpropan-1,2-diamine hydrochloride Example 246A was added to the reaction mixture, and stirring was continued at RT overnight. . The mixture was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 219 mg (79% of theory, 99% purity) of the target compound.

LC-MS (Method 2): R _t = 0.79min

MS (ESI +): m / z = 457 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.19 (s, 3H), 2.31 (s, 3H), 2.53 (s, 3H; overlap with DMSO peak), 3.41-3.49 (m, 1H), 3.53 -3.61 (m, 1H), 5.29 (s, 2H), 6.94 (s, 1H), 7.20-7.28 (m, 2H), 7.59 (quintet, 1H), 7.78 (t, 1H), 8.48 (s , 1H).

Example 240 Enantiomer-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methyl-imidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

210 mg of Example 239 was separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 x 20 mm, mobile phase: 25% isohexane, 75% isopropanol Flow rate: 20ml / min; 23 ° C, detection: 210nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer A: Yield: 63 mg (100% ee)

R _t = 6.53min [Daicel Chiralcel OZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 241 Enantiomer-N- (2-amino-3,3,3-trifluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methyl-imidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

210 mg of Example 239 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 x 20 mm, mobile phase: 25% iso Hexane, 75% isopropanol; flow rate: 20 ml / min; 23 ° C, detection: 210 nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 30 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer B: Yield: 50 mg (92% ee)

R _t = 7.07min [Daicel Chiralcel OZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection: 220nm ].

Example 242 Enantio-N- (2-amino-3-methoxypropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

100 mg (0.29 mmol, 96% purity) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A was first placed in DMF (1.84 ml), 121 mg (0.32 mmol) of HATU and 0.15 ml (0.87 mmol) of N, N-diisopropylethylamine were added and the mixture was stirred at RT for 20 min. 72 mg (0.40 mmol) of enantio-3-methoxypropan-1,2-diamine dihydrochloride (mirror isomer A) Example 249A was dissolved in 0.48 ml of DMF, and 0.30 ml (1.73 mmol) was added. N, N-diisopropylethylamine and the mixture was stirred at RT for 10 min. This solution was then added to the previously prepared reaction solution at -20 ° C, and the reaction mixture was stirred at RT overnight. The mixture was then diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water ladder). Add 0.1% TFA). The product was concentrated and the fractions were concentrated. Dichloromethane / ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the residue. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. This gave 77 mg (63% of theory, 99% purity) of the target compound.

LC-MS (Method 2): R _t = 0.67min

MS (ESI +): m / z = 419 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 2.31 (s, 3H), 3.09-3.16 (m, 1H), 3.19-3.27 (m, 2H), 3.28 (s, 3H), 3.38-3.44 ( m, 2H; overlap with water signal), 5.28 (s, 2H), 6.92 (s, 1H), 7.18-7.29 (m, 2H), 7.54-7.65 (m, 1H), 7.74 (t, 1H), 8.50 (s, 1H), [additional signal under DMSO peak].

Example 243 Enantio-N- (2-amino-3-methoxypropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

Preparation and purification of the title compound was performed similar to Example 242. At 100 mg (0.29 mmol, 96% purity) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A and 72 mg (0.40 mmol) of enantio-3-methoxypropane-1,2-diamine dihydrochloride (mirror isomer B) Example 250A was used as starting material to obtain 63 mg (51% of theory Value, purity 99%) Target compound.

LC-MS (Method 2): R _t = 0.67min

MS (ESI +): m / z = 419 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.95-2.25 (br.s, 2H), 2.31 (s, 3H), 3.02-3.10 (m, 1H), 3.15-3.25 (m, 2H), 3.27-3.41 (m, 5H; overlap with water signal), 5.28 (s, 2H), 6.92 (s, 1H), 7.19-7.28 (m, 2H), 7.55-7.64 (m, 1H), 7.72 (t, 1H), 8.49 (s, 1H).

Example 244 Racemic-N- (2-amino-2-methylpentyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide

Add 191 mg (0.62 mmol) of TBTU and 0.25 ml (2.27 mmol) of 4-methylmorpholine and 72 mg (0.62 mmol) of racemic 2-methylpentan-1,2-diamine Example 16A to 200 mg (0.57 mmol) of 6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid in DMF (2.0 ml) solution, and the reaction mixture was stirred at RT overnight. Then 36 mg (0.31 mmol) of racemic-2-methylpentan-1,2-diamine and 0.06 ml (0.57 mmol) of 4-methylmorpholine were added and stirring was continued at RT overnight. The mixture was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (dichloro Methane / methanol: 10: 1, then dichloromethane / 2N ammonia methanol solution 20: 1). This gave 189 mg (73% of theory, 99% purity) of the target compound.

LC-MS (Method 2): R _t = 0.78min

MS (ESI +): m / z = 451 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.83-0.89 (m, 3H), 0.99 (s, 3H), 1.22-1.42 (m, 4H), 1.52-1.88 (br.s, 2H), 2.55 (s, 3H; superimposed by DMSO peak), 3.15-3.26 (m, 2H), 5.35 (s, 2H), 7.20 (d, 1H), 7.22-7.29 (m, 2H), 7.56-7.65 (m, 1H), 7.67-7.82 (br.s, 1H), 8.76 (d, 1H).

Example 245 Enantio-N- (2-amino-2-methylpentyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

182 mg of Example 244 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 30 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 40ml / min; 25 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C). The product was then purified again by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

Mirror isomer A: Yield: 30 mg (88% ee)

R _t = 7.90min [Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 35 ° C; detection: 220nm ].

Specific rotation [α] (589nm, 19.7 ℃) =-2.6 ° (c = 0.005g / ml, acetonitrile)

Example 246 Enantio-N- (2-amino-2-methylpentyl) -6-chloro-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

182 mg of Example 244 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AZ-H, 5 μm, 250 x 30 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine, flow rate: 40ml / min; 25 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C). The product was then purified again by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

Mirror isomer B: Yield: 24 mg (77% ee)

R _t = 9.07min [Daicel Chiralpak AZ-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 35 ° C; detection: 220nm ].

Specific rotation [α] (589nm, 19.9 ℃) = + 2.5 ° (c = 0.0048g / ml, acetonitrile)

Example 247 Enantiomer-N- (2-amino-3-methoxypropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] -Pyridine-3-carboxamide (mirror isomer A)

Preparation and purification of the title compound was performed similar to Example 242. 100 mg (0.31 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A and 78 mg (0.44 mmol ) Enantiomer-3-methoxypropane-1,2-diamine dihydrochloride (mirror isomer A) Example 249A was used as starting material to obtain 76 mg (59% of theoretical value, purity 98%). Target compound.

LC-MS (Method 2): R _t = 0.62min

MS (ESI +): m / z = 405 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.57-1.87 (br.s, 2H), 2.53 (s, 3H; overlap with DMSO peak), 3.00-3.08 (m, 1H), 3.14-3.25 ( m, 2H), 3.26-3.42 (m, 5H; overlap with water signal), 5.30 (s, 2H), 6.93 (t, 1H), 7.01 (d, 1H), 7.19-7.28 (m, 2H), 7.54 -7.64 (m, 1H), 7.75 (t, 1H), 8.65 (d, 1H).

Example 248 Enantiomer-N- (2-amino-3-methoxypropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] -Pyridine-3-carboxamide (mirror isomer B)

Preparation and purification of the title compound was performed similar to Example 242. 100 mg (0.31 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A and 78 mg (0.44 mmol ) Enantiomer-3-methoxypropan-1,2-diamine dihydrochloride (mirror isomer B) Example 250A was used as starting material to obtain 72 mg (56% of theoretical value, purity 99%). Target compound.

LC-MS (Method 2): R _t = 0.62min

MS (ESI +): m / z = 405 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.56-1.85 (br.s, 2H), 2.53 (s, 3H; overlap with DMSO peak), 3.00-3.07 (m, 1H), 3.14-3.26 ( m, 2H), 3.26-3.42 (m, 5H; overlap with water signal), 5.30 (s, 2H), 6.93 (t, 1H), 7.01 (d, 1H), 7.19-7.28 (m, 2H), 7.54 -7.64 (m, 1H), 7.75 (t, 1H), 8.66 (d, 1H).

Example 249 Racemic-N- (2-amino-2,4-dimethylpentyl) -2,6-dimethyl-8- (3-methylbutoxy) imidazo [1,2-a ] Pyridine-3-carboxamide

175 mg (0.63 mmol) of 2,6-dimethyl-8- (3-methylbutoxy) imidazo [1,2-a] pyridine-3-carboxylic acid Example 252A was first placed in DMF (2.2 ml ), 214 mg (0.67 mmol) of TBTU, 0.28 ml (2.53 mmol) of 4-methylmorpholine and 91 mg (0.70 mmol) of racemic-2,4-dimethylpentane-1,2- Diamine and stir the reaction mixture at RT overnight. The mixture was diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). After concentration, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 225 mg (90% of theory, 98% purity) of the target compound.

LC-MS (Method 7): R _t = 0.62min

MS (ESI +): m / z = 389 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.90-0.98 (m, 12H), 1.07 (s, 3H), 1.25-1.38 (m, 2H), 1.65-1.73 (m, 2H), 1.75- 1.88 (m, 2H), 2.27 (s, 3H), 2.57 (s, 3H), 3.18-3.29 (m, 2H), 4.15 (t, 2H), 6.71 (s, 1H), 7.66 (t, 1H) , 8.42 (s, 1H).

Example 250 Racemic-8-[(2,6-difluorobenzyl) oxy] -2-methyl-N- (1,2,3,4-tetrahydroquinolin-2-ylmethyl) imidazo [1,2-a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 235. 190 mg (0.34 mmol) of racemic-2-{[({8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3 -Yl} carbonyl) amino] methyl} -3,4-dihydroquinoline-1 (2H) -carboxylic acid tert-butyl ester Example 253A as starting material, 149 mg (93% of theory, purity 98) %) Of the target compound.

LC-MS (Method 2): R _t = 0.99min

MS (ESI +): m / z = 463 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.56-1.67 (m, 1H), 1.86-1.95 (m, 1H), 2.66-2.73 (m, 2H), 3.37-3.50 (m, 3H), 5.31 (s, 2H), 5.70-5.77 (m, 1H), 6.43 (t, 1H), 6.48 (d, 1H), 6.82-6.89 (m, 2H), 6.95 (t, 1H), 7.03 (d, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.96 (t, 1H), 8.64 (d, 1H), [additional signal under solvent peak].

Example 251 Enantio-N-[(1R, 2R) -2-aminocyclohexyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 235. With 107 mg (0.2 mmol, 98% purity) of the enantiomer-{(1R, 2R) -2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Imidazolo [1,2-a] pyridin-3-yl} carbonyl) amino] cyclohexyl} carbamic acid third butyl ester Example 254A was used as starting material to obtain 83 mg Target compound.

LC-MS (Method 7): R _t = 0.59min

MS (ESI +): m / z = 429 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.08-1.35 (m, 4H), 1.61-1.72 (m, 2H), 1.81-1.89 (m, 1H), 1.90-1.97 (m, 1H), 2.30 (s, 3H), 3.45-3.56 (m, 1H), 5.28 (s, 2H), 6.89 (s, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.67 ( d, 1H), 8.37 (s, 1H), [additional signal under solvent peak].

Example 252 N- (2-amino-2-ethylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine -3-carboxamide

Add 70 mg (0.60 mmol) of 2-ethylbutyl-1,2-diamine to 100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl In a solution of Example 21A of imidazo [1,2-a] pyridine-3-carboxylic acid, 145 mg (0.45 mmol) of TBTU, and 0.13 ml (1.20 mmol) of 4-methylmorpholine in DMF, The reaction mixture was stirred at RT overnight. The mixture was then diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). After concentration, the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 110 mg (85% of theory, 100% purity) of the target compound.

LC-MS (Method 2): R _t = 0.60min

MS (ESI +): m / z = 431 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.82 (t, 6H), 1.22-1.49 (m, 6H), 2.31 (s, 3H), 2.52 (s, 3H; overlap with DMSO peak), 3.17 -3.23 (m, 2H), 5.28 (s, 2H), 6.91 (s, 1H), 7.19-7.28 (m, 2H), 7.51 (t, 1H), 7.55-7.64 (m, 1H), 8.50 (s , 1H).

Example 253 N- (2-amino-2-ethylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3- Carboxamide

The title compound was prepared and purified similarly to Example 252. 75 mg (0.24 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A and 41 mg (0.35 mmol ) 2-ethylbutyl-1,2-diamine as a starting material, and 73 mg (74% of the theoretical value, 99% purity) of the target compound were obtained.

LC-MS (Method 2): R _t = 0.64min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.83 (t, 6H), 1.26-1.43 (m, 4H), 1.89 (br.s, 2H), 2.56 (s, 3H; overlap with DMSO signal) , 3.20-3.26 (m, 2H), 5.31 (s, 2H), 6.94 (t, 1H), 7.01 (d, 1H), 7.23 (t, 2H), 7.50-7.64 (m, 2H), 8.68 (d , 1H).

Example 254 Racemic-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] -Pyridine-3-carboxamide

The title compound was prepared and purified similarly to Example 252. 120 mg (0.38 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 3A and 58 mg (0.57 mmol ) Racemic-2-methylbutyl-1,2-diamine as a starting material, 98 mg (63% of theoretical value, purity 98%) of the target compound were obtained.

LC-MS (Method 2): R _t = 0.58min

MS (ESI +): m / z = 403 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 0.97 (s, 3H), 1.28-1.39 (m, 2H), 1.40-1.49 (br s., 2H), 2.56 ( s, 3H; overlap with DMSO signal), 3.14-3.27 (m, 2H), 5.30 (s, 2H), 6.94 (t, 1H), 7.01 (d, 1H), 7.19-7.27 (m, 2H), 7.54 -7.69 (m, 2H), 8.65 (d, 1H).

Example 255 N- [2- (Third-butylamino) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] -Pyridine-3-carboxamide

70 mg (0.21 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A, 71 mg (0.22 mmol) of TBTU and 128 mg (1.26 mmol) of 4-methylmorpholine were first placed in DMF (0.74 ml), and 44 mg (0.23 mmol) of N-tert-butylethyl-1,2-di Amine dihydrochloride and the reaction mixture was stirred at RT overnight. Another 22 mg (0.12 mmol) of N-tert-butylethyl-1,2-diamine dihydrochloride and 21 mg (0.21 mmol) of 4-methylmorpholine were added, and the mixture was stirred at RT for 1.5 h . The mixture was diluted with a few drops of water / TFA and purified by preparative RP-HPLC (0.1% TFA in acetonitrile / water) and the product was concentrated in fractions. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 78 mg (86% of theory, 96% purity) of the target compound.

LC-MS (Method 2): R _t = 0.66min

MS (ESI +): m / z = 431 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.18 (br.s, 9H), 2.32 (s, 3H), 2.52 (s, 3H, hidden by DMSO signal), 2.70-3.12 (br.s, 2H), 3.38-3.62 (m, 2H), 5.29 (s, 2H), 6.92 (s, 1H), 7.20-7.27 (m, 2H), 7.59 (five-fold peak, 1H), 7.74 (br.s, 1H), 8.34 (br.s, 1H), 8.53 (s, 1H).

Example 256 Enantio-N- (2-amino-2-methylpropyl) -8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer B)

84 mg (0.24 mmol) of enantiomer-8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1,2-a] pyridine-3- Example 257A of carboxylic acid was first placed in DMF (1.54 ml), and 117 mg (0.36 mmol) of TBTU, 98 mg (0.97 mmol) of 4-methylmorpholine and 43 mg (0.49 mmol) of 2-methylpropan-1 , 2-diamine and the reaction mixture was stirred at RT overnight. The mixture was then purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA) and the product fractions were concentrated. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was dried under high vacuum and then lyophilized. This gave 85 mg (84% of theory, 99% purity) of the target compound.

LC-MS (Method 13): R _t = 1.48min

MS (ESI +): m / z = 417 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6H), 1.61-1.74 (m, 2H), 1.78 (d, 3H), 2.18 (s, 3H), 2.57 (s, 3H) , 3.19 (d, 2H), 6.20 (q, 1H), 6.56 (s, 1H), 7.06-7.14 (m, 2H), 7.37-7.46 (m, 1H), 7.69 (t, 1H), 8.40 (s , 1H).

Example 257 N- (2-amino-2-methylpentyl) -8- [1- (2,6-difluorophenyl) ethoxy] -2,6-dimethylimidazo [1,2- a] pyridine-3-carboxamide

Add 16 mg (0.14 mmol) of racemic-2-methylpentan-1,2-diamine to 40 mg (0.12 mmol) of enantio-8- [1- (2,6-difluorophenyl) ethyl Oxy] -2,6-dimethylimidazo [1,2-a] -pyridine-3-carboxylic acid Example 257A, 45 mg (0.14 mmol) of TBTU, and 47 mg (0.46 mmol) of 4-methylmorphine In a solution of phthaloline in DMF (0.77 ml), the reaction mixture was stirred at RT overnight. A few drops of water / TFA were added and the mixture was purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. The residue was treated in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, concentrated, dried under high vacuum and then lyophilized. This gave 27.4 mg (52% of theory, 97% purity) of the target compound.

LC-MS (Method 2): R _t = 0.71min

MS (ESI +): m / z = 445 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.98 (s, 3H), 1.22-1.39 (m, 4H), 1.48 (br.s, 2H), 1.78 (d, 3H), 2.19 (s, 3H), 2.57 (s, 3H), 3.13-3.26 (m, 2H), 6.20 (q, 1H), 6.56 (s, 1H), 7.06-7.14 (m, 2H), 7.37 -7.44 (m, 1H), 7.58-7.64 (m, 1H), 8.41 (s, 1H).

Example 258 Racemic-N- (2-amino-2,4-dimethylpentyl) -2,6-dimethyl-8- [4,4,4-trifluoro-3- (trifluoromethyl ) Butoxy] -imidazo [1,2-a] pyridine-3-carboxamide

31 mg (0.08 mmol) of 2,6-dimethyl-8- [4,4,4-trifluoro-3- (trifluoromethyl) butoxy] imidazo [1,2-a] pyridine- 3-carboxylic acid example 259A (dissolved in 0.3 ml of DMF), 40 mg (0.104 mmol) of HATU (dissolved in 0.3 ml of DMF), and then 16 mg (0.16 mmol) of 4-methylmorpholine was added to 10 mg ( 0.08 mmol) in racemic-2,4-dimethylpentane-1,2-diamine. The mixture was shaken at RT overnight. The target compound was concentrated by preparative HPLC (Method 12). This gave 10 mg (25% of theory).

LC-MS (Method 8): R _t = 0.78min

MS (ES +): m / z = 497 (M + H) ⁺

Example 259 Racemic-N- (2-amino-2-cyclopropylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1, 2-a] pyridine-3-carboxamide

160 mg (0.48 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A, 162 mg (0.51 mmol) of TBTU and 292 mg (2.89 mmol) of 4-methylmorpholine were first placed in DMF (1.7 ml), and 99 was added at 0 ° C. mg (0.53 mmol) of racemic-2-cyclopropylpropan-1,2-diamine dihydrochloride. The reaction mixture was allowed to warm to room temperature and then stirred at RT overnight. An additional 50 mg (0.27 mmol) of 2-cyclopropylpropan-1,2-diamine dihydrochloride and 49 mg (0.48 mmol) of 4-methylmorpholine were added, and the mixture was stirred at RT for 1.5 h. The mixture was diluted with a few drops of water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with addition of 0.1% TFA). The product was concentrated and the fractions were concentrated. A saturated aqueous sodium bicarbonate solution was added to the residue and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 156 mg (76% of theory) of the target compound.

LC-MS (Method 2): R _t = 0.63min

MS (ESI +): m / z = 429 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.18-0.38 (m, 4H), 0.79-0.88 (m, 1H), 0.97 (s, 3H), 1.13-1.36 (m, 2H), 2.31 ( s, 3H), 2.54 (s, 3H, hidden by DMSO signal), 3.20-3.3.26 (m, 1H), 3.30-3.38 (m, 1H), 5.29 (s, 2H), 6.91 (s, 1H) , 7.19-7.27 (m, 2H), 7.54-7.63 (m, 2H), 8.50 (s, 1H).

Example 260 Enantio-N- (2-amino-2-cyclopropylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

140mg of Example 259 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine, flow rate: 17ml / min; 40 ° C, detection: 210nm].

Mirror isomer A: Yield: 48 mg (100% ee)

R _t = 8.53min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Specific rotation [α] (365nm, 20.5 ℃) =-8.4 ° (c = 0.005g / ml, acetonitrile)

Example 261 Enantio-N- (2-amino-2-cyclopropylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

140mg of Example 259 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak AD-H, 5 μm, 250 x 20mm, mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate: 17ml / min; 40 ° C, detection: 210nm].

Mirror isomer B: Yield: 38 mg (90% ee)

R _t = 9.12min [Daicel Chiralpak AD-H, 5μm, 250 x 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm ].

Example 262 Racemic-N- [2-amino-4- (benzyloxy) -2-methylbutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide

Add 503 mg (1.32 mmol) of HATU and 1.05 ml (6.0 mmol) of N, N-diisopropylethylamine in DMF (7.7 ml) to 400 mg (1.2 mmol) of 8-[(2,6- Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid Example 21A, and the mixture was stirred at RT for 20 min. 300 mg (1.38 mmol) of racemic-4- (benzyloxy) -2-methylbutyl-1,2-diamine Example 261A was dissolved in 2 ml of DMF and added to the reaction solution at 0 ° C. The mixture was stirred at 0 ° C for 1 h and then diluted with water / TFA and purified by preparative RP-HPLC (acetonitrile / water gradient with 0.1% strength TFA). This gave 600 mg (88% of theory, 93% purity) of the target compound.

LC-MS (Method 2): R _t = 0.78min

MS (ESI +): m / z = 523 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.30 (s, 3H), 1.87-2.01 (m, 2H), 2.36 (s, 3H), 2.56 (s, 3H), 3.47-3.70 (m, 4H), 4.50 (s, 2H), 5.34 (s, 2H), 7.12-7.38 (m, 8H), 7.55-7.64 (m, 1H), 7.73 (br.s, 2H), 8.08 (br.s, 1H), 8.55 (s, 1H).

The examples shown in Table 14 are similar to Example 262 with the appropriate carboxylic acid (Examples 3A and 21A) and an appropriate prepared or commercially available amine (1.05-2.5 equivalents) and N, N-diisopropylethylamine as described above. (3-6 equivalents) Prepared by reaction under the reaction conditions described in General Procedure 3.

Exemplary follow-up of the reaction mixture: Water is added to the reaction solution and the mixture is extracted three times with ethyl acetate or dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). Alternatively, the precipitation or reaction mixture can be further processed directly by preparative HPLC Purified (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA) and dried under high vacuum overnight. If appropriate, the product fractions are treated in ethyl acetate or dichloromethane and washed twice with saturated aqueous sodium bicarbonate. The aqueous phase is extracted twice with ethyl acetate or dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated.

Example 266 Enantiomer-N- [2-amino-4- (benzyloxy) -2-methylbutyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

637 mg of Example 264 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OD-H, 5 μm, 250 x 20 mm, mobile phase: 100% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm].

Mirror isomer A: Yield: 267 mg (99% ee)

R _t = 5.45min [Daicel Chiralcel OD-H, 5μm, 250 x 4.6mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm].

Example 267 Enantiomer-N- [2-amino-4- (benzyloxy) -2-methylbutyl] -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

637 mg of Example 264 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OD-H, 5 μm, 250 x 20 mm, mobile phase: 100% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm].

Mirror isomer B: Yield: 292 mg (99% ee)

R _t = 7.10min [Daicel Chiralcel OD-H, 5 μm, 250 x 4.6mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 220nm].

Example 268 Enantio-N- (2-amino-3-hydroxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

460 mg of Example 265 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 x 20 mm, mobile phase: 100% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 15 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Intermediate enantiomer -N-[(2R) -2-amino-3- (benzyloxy) -2-methylpropyl] -8-[(2,6-difluorobenzyl) oxy]- Yield of 2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A): 183 mg (99% ee).

R _t = 6.61min [Daicel Chiralcel OZ-H, 5 μm, 250 x 4.6mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 235nm].

Under argon, 183 mg (0.36 mmol) of enantio-N-[(2R) -2-amino-3- (benzyloxy) -2-methylpropyl] -8-[(2,6 -Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A) was first placed in 3.7 ml of ethanol and 38.3 mg of activated carbon on palladium (10%) and 1.09 ml (10.8 mmol) of cyclohexene. The reaction mixture was stirred at reflux for 6 h. The reaction mixture was applied directly to diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / methanol 10/1, dichloromethane / 2N ammonia methanol solution 10/1). Thus 80 mg of the target compound were obtained (52% of theory; 98% purity).

LC-MS (Method 2): R _t = 0.61min

MS (ESI +): m / z = 419 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.97 (s, 3H), 1.92 (br.s, 2H), 2.31 (s, 3H), 2.54 (s, 3H, hidden by DMSO signal), 3.15 -3.32 (m, 4H), 4.73-4.82 (m, 1H), 5.28 (s, 2H), 6.92 (s, 1H), 7.22 (t, 2H), 7.53-7.66 (m, 2H), 8.51 (s , 1H).

Example 269 Enantio-N- (2-amino-3-hydroxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

460 mg of Example 265 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 x 20 mm, mobile phase: 100% ethanol + 0.2% diethylamine, Flow rate: 15ml / min; 40 ° C, detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 15 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Intermediate enantiomer -N-[(2R) -2-amino-3- (benzyloxy) -2-methylpropyl] -8-[(2,6-difluorobenzyl) oxy]- Yield of 2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B): 189 mg (99% ee).

R _t = 8.47min [Daicel Chiralcel OZ-H, 5μm, 250 x 4.6mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 235nm].

Under argon, 189 mg (0.37 mmol) of enantio-N-[(2R) -2-amino -3- (benzyloxy) -2-methylpropyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridine-3-carboxamide (mirror isomer B) was first placed in 3.8 ml of ethanol, and 39.5 mg of activated carbon on palladium (10%) and 1.13 ml (11.2 mmol) of cyclohexene were added. The reaction mixture was stirred at reflux for 12 h. The reaction mixture was applied directly to diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / methanol 10/1, dichloromethane / 2N ammonia methanol solution 10/1). This gave 85 mg of the target compound (54% of theory; 98% purity).

LC-MS (Method 2): R _t = 0.52min

MS (ESI +): m / z = 419 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.97 (s, 3H), 1.83 (br.s, 2H), 2.30 (s, 3H), 2.54 (s, 3H, hidden by DMSO signal), 3.15 -3.32 (m, 4H), 4.73-4.82 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.22 (t, 2H), 7.53-7.66 (m, 2H), 8.51 (s , 1H).

Example 270 Racemic-N- (2-amino-4-hydroxy-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

Under argon, 295 mg (0.52 mmol) of racemic-N- [2-amino-4- (benzyloxy) -2-methylbutyl] -8-[(2,6-difluorobenzyl) ) Oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide Example 262 was first placed in 5.4 ml of ethanol and 56 mg of Pd / carbon (10% ) And the mixture was hydrogenated at room temperature for 6.5 h. The reaction mixture was left under hydrogen until overnight. The reaction mixture was applied to silica gel, concentrated and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution 10/1 isocratic). This gave 95 mg of the target compound (42% of theory).

LC-MS (Method 2): R _t = 0.70min

MS (ESI +): m / z = 433 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.07 (s, 3H), 1.49-1.68 (m, 2H), 2.31 (s, 3H), 2.54 (s, 3H, hidden by DMSO signal), 3.26 (br.s, 2H), 3.51-3.68 (m, 2H), 5.28 (s, 2H), 6.91 (s, 1H), 7.22 (t, 2H), 7.53-7.70 (m, 2H), 8.50 (s , 1H).

Example 271 Enantio-N- (2-amino-4-hydroxy-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

187 mg of Example 270 was separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 x 20 mm; mobile phase: 50% isohexane, 50% ethanol + 0.2 % Diethylamine; flow rate: 15ml / min; 40 ° C; detection: 220nm]. The product fractions were collected on dry ice, combined and concentrated on a rotary evaporator (bath temperature 30 ° C) to a residue volume of about 15 ml, and about 60 ml of water was added. The resulting solution was frozen and lyophilized.

Mirror isomer A: Yield: 63 mg (99% ee)

R _t = 5.57min [Daicel Chiralcel OZ-H, 5μm, 250 x 4.6mm; mobile phase: 100% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; 40 ° C; detection: 235nm].

Specific rotation [α] (365nm, 20.2 ℃) =-8.3 ° (c = 0.005g / ml, acetonitrile)

Example 272 Enantio-N- (2-amino-4-hydroxy-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

Under argon, 257 mg (0.51 mmol) of enantio-N- [2-amino-4- (benzyloxy) -2-methylbutyl] -8-[(2,6-difluorobenzyl) ) Oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A) Example 266 was first placed in 5.2 ml of ethanol, and 54 mg of activated carbon was added. Palladium (10%) and 1.54 ml (15.2 mmol) of cyclohexene were applied, the reaction mixture was stirred at reflux for 6.5 h and then applied to celite and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia Methanol solution 20/1). This gave 122 mg of the target compound (56% of theory; 98% purity).

LC-MS (Method 2): R _t = 0.60min

MS (ESI +): m / z = 419 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 1.03 (s, 3H), 1.46-1.62 (m, 2H), 1.71 (br.s, 2H), 2.55 (s, 3H, hidden by DMSO signal) , 3.19-3.28 (m, 2H), 3.52-3.68 (m, 2H), 4.75 (br.s, 1H), 5.30 (s, 2H), 6.92 (t, 1H), 7.00 (d, 1H), 7.22 (t, 2H), 7.59 (quintet, 1H), 7.63-7.73 (m, 1H), 8.67 (d, 1H).

Example 273 Racemic-N- (2-amino-3-hydroxy-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1, 2-a] pyridine-3-carboxamide

800 mg (1.57 mmol) of racemic-N- [2-amino-3- (benzyloxy) -2-methylpropyl] -8-[(2,6-difluoro Benzyl) oxy] -2-methylimidazo [1,2-a] pyridine-3-carboxamide Example 263 was first placed in 16.2 ml of ethanol, and 167 mg of activated carbon (10%) And 4.77 ml (47.1 mmol) of cyclohexene. The reaction mixture was stirred at reflux for 18 h and then applied to diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / methanol 10/1, dichloromethane / 2N ammonia methanol solution 10/1). This gave 366 mg of the target compound (56% of theory; 97% purity).

LC-MS (Method 2): R _t = 0.54min

MS (ESI +): m / z = 405 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.96 (s, 3H), 1.79 (br.s, 2H), 2.56 (s, 3H, overlap with DMSO signal), 3.19-3.33 (m, 4H; Overlapping with water signal), 4.74-4.80 (m, 1H), 5.30 (s, 2H), 6.92 (t, 1H), 7.01 (d, 1H), 7.22 (t, 2H), 7.55-7.69 (m, 2H ), 8.69 (d, 1H).

Example 274 Enantiomer-N- (2-amino-2-methylbutyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1, 2-a] pyridine-3-carboxamide (mirromeric isomer A)

Under argon, 383 mg (0.56 mmol) of the enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [ 1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer A) Example 278A was first placed in 5.75 ml of ethanol and 39 mg of activated carbon on palladium (II) hydroxide (20%). Place the reaction mixture at RT Hydrogenated under quasi-pressure for 2h, applied to diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). This gave 208 mg of the target compound (85% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ESI +): m / z = 435 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 0.97 (s, 3H), 1.31-1.39 (m, 2H), 1.42 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H, overlap with DMSO signal), 3.14-3.26 (m, 2H), 5.34 (s, 2H), 6.92 (s, 1H), 7.25-7.34 (m, 1H), 7.58-7.72 (m, 2H), 8.49 (s, 1H).

Single crystal X-ray structure analysis confirmed that this mirror isomer is of S configuration.

Example 275 Enantiomer-N- (2-amino-2-methylbutyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer B)

Under argon, 200 mg (0.29 mmol) of the enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [ 1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester trifluoroacetate (mirror isomer B) Example 279A First put 3.0 ml of ethanol and 10.3 mg of activated carbon on palladium (II) hydroxide (20%). The reaction mixture was hydrogenated at RT and atmospheric pressure for 6 h. Another 10.3 mg of activated carbon was added with palladium (II) hydroxide (20%), and the mixture was hydrogenated at RT for 1 h. The reaction mixture was applied to diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). This gave 92 mg of the target compound (72% of theory).

LC-MS (Method 2): R _t = 0.66min

MS (ESI +): m / z = 435 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.98 (s, 3H), 1.32-1.41 (m, 2H), 1.81 (br.s, 2H), 2.31 (s, 3H), 2.54 (s, 3H, overlap with DMSO signal), 3.15-3.28 (m, 2H), 5.34 (s, 2H), 6.92 (s, 1H), 7.25-7.34 (m, 1H), 7.59-7.73 (m, 2H), 8.49 (s, 1H).

Example 276 N- (2-amino-2-methylpropyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a ] Pyridine-3-carboxamide

70 mg (0.20 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylic acid Example 265A 84 mg (0.22 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU) and 77 mg (0.60 mmol) of N, N-diisopropylethylamine were dissolved in 1.3 ml of DMF, and after 20 min at 0 ° C, 19.4 mg (0.22 mmol) of 2-methylpropane was added -1,2-diamine. The mixture was stirred at 0 ° C for 45 min and then purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The resulting product fractions were treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 54 mg (64% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.65min

MS (ES +): m / z = 421 (M + H) ⁺

¹ H NMR (500MHz, DMSO-d ₆ ): δ = 1.05 (s, 6 H), 1.93 (br.s, 2 H), 2.30 (s, 3 H), 2.54 (s, 3 H; and DMSO peak Overlapping), 3.21 (d, 2 H), 5.32 (s, 2 H), 6.92 (s, 1 H), 7.27-7.32 (m, 1 H), 7.62-7.74 (m, 2 H), 8.48 (s , 1 H).

Example 277 Racemic-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -7-fluoro-2-methylimidazo [1, 2-a] pyridine-3-carboxamide

50 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl) oxy] -7-fluoro-2-methylimidazo [1,2-a] pyridine-3-carboxylic acid Example 270A, 62 mg (0.16 mmol) of O- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethylhexafluorophosphate (HATU) and 58 mg (0.45 mmol) of N, N-diisopropylethylamine were dissolved in 1.0 ml of DMF, and after 20 min at 0 ° C, 21.4 mg (0.18 mmol) of 2-methylpentane was added -1,2-diamine. The mixture was stirred at 0 ° C for 1.5 h, acetonitrile / TFA was added and the mixture was purified by preparative HPLC (method: RP18 column, mobile phase: acetonitrile / water gradient addition of 0.1% TFA). The resulting product fraction was treated in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 31 mg (45% of theory; 94% purity) of the title compound.

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 435 (M + H) ⁺

1H NMR (400MHz, DMSO-d6): δ = 0.83-0.92 (m, 3 H), 1.02 (s, 3 H), 1.26-1.43 (m, 4 H), 1.87 (br.s, 2 H), 2.63 (s, 3 H), 3.15-3.30 (m, 2 H), 5.60 (s, 2 H), 6.97-7.06 (m, 1 H), 7.08-7.18 (m, 2 H), 7.51 (five-fold peak, 1 H), 7.64-7.78 (m, 1 H), 8.77 (dd, 1 H).

Example 278 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer B)

Under argon, 9 mg of 20% palladium (II) hydroxide on carbon was added to 180 mg (0.26 mmol) of the enantiomer from Example 290A- {1-[({8-[(2,6-difluorobenzyl) ) Oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl Ester trifluoroacetate in 2.8 ml of ethanol solution, and the mixture was hydrogenated at RT and standard pressure for 2 h. The reaction mixture was filtered, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). The separated product was separated by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution, and the combined aqueous phase was extracted twice with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was lyophilized. This gave 73 mg of the target compound (63% of theory).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 447 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.99 (s, 3H), 1.23-1.41 (m, 4H), 2.53 (s, 3H), 3.14-3.26 (m , 2H), 3.79 (s, 3H), 5.30 (s, 2H), 6.87 (d, 1H), 7.24 (quin., 2H), 7.54-7.65 (m, 2H), 8.37 (d, 1H).

Example 279 Enantio-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -6-methoxy-2-methylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer A)

Under argon, 8 mg of 20% palladium (II) hydroxide on carbon was added to 157 mg (0.23 mmol) of the enantiomer- {1-[({8-[(2,6-difluorobenzyl) ) Oxy] -6-methoxy-2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl Ester trifluoroacetate (mirromeric isomer A) in 2.5 ml of ethanol, and the mixture was hydrogenated at RT and standard pressure for 2 h. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). This gave 90 mg of the target compound (90% of theory).

LC-MS (Method 2): R _t = 0.63min

MS (ES +): m / z = 433 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.97 (s, 3H), 1.31-1.39 (m, 2H), 1.40-1.49 (m, 2H), 2.53 (s , 3H), 3.14-3.27 (m, 2H), 3.79 (s, 3H), 5.30 (s, 2H), 6.87 (d, 1H), 7.24 (quin, 2H), 7.54-7.64 (m, 2H), 8.39 (d, 1H).

Example 280 Enantiomer-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-methyl-6- (morpholine-4- Yl) imidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer B)

Under argon, 1.2 mg of 20% palladium (II) hydroxide on carbon was added to 22 mg (0.04 mmol) of the enantiomer-1-[({8-[(2,6-difluorobenzyl) from Example 293A ) Oxy] -2-methyl-6- (morpholinolin-4-yl) imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2- Benzylcarbamate (Mirror Isomer B) in 0.38 ml of an ethanol solution, and the mixture was hydrogenated at RT and standard pressure for 2 h. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 20/1). This gave 9 mg of the target compound (48% of theory; purity 92%).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 502 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.98 (s, 3H), 1.26-1.36 (m, 2H), 1.38-1.45 (m, 2H), 2.55-2.57 (s, 3H, hidden under the solvent peak), 3.05 (t, 4H), 3.16-3.22 (m, 2H), 3.77 (t, 4H), 5.31 (s, 2H), 6.99-7.05 (m, 1H) , 7.20-7.28 (m, 2H), 7.54-7.64 (m, 2H), 8.20 (s, 1H).

Example 281 Enantiomer-N- (2-amino-2-methylpentyl) -6-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1 , 2-a] pyridine-3-carboxamide (mirror isomer B)

Under argon, 7.8 mg of 10% palladium on carbon was added to 5.52 mg (0.07 mmol) of the enantiomer-{1-[({6-cyclopropyl-8-[(2,6-di Fluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoro Acetate (mirror isomer B) in 0.76 ml of ethanol, and the mixture was hydrogenated at RT and standard pressure for 1 h. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated and dried under high vacuum. The product was purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). This gave 27 mg of the target compound (76% of theory).

LC-MS (Method 2): R _t = 0.79min

MS (ES +): m / z = 457 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.72-0.77 (m, 2H), 0.87 (t, 3H), 0.90-0.97 (m, 2H), 0.99 (s, 3H), 1.22-1.42 (m, 4H), 1.43-1.51 (m, 2H), 1.94-2.03 (m, 1H), 2.52 (s, 3H), 3.13-3.26 (m, 2H), 5.31 (s, 2H), 6.68 (s , 1H), 7.23 (quin, 2H), 7.54-7.66 (m, 2H), 8.50 (s, 1H).

Example 282 Racemic-N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamidate

Under argon, add 1.4 mg (0.01 mmol, 20%) of palladium (II) hydroxide to 54 mg (0.09 mmol) of the racemic- {1-[({8-[(2,6) -Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-fluoro-2-methylpropan-2- In a 5 ml ethanol solution of benzyl carbamate, and the reaction mixture was hydrogenated at standard pressure overnight. The mixture was then filtered through celite, the filter cake was washed with ethanol and the filtrate was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated on a rotary evaporator. This gave 18.4 mg of the target compound (40% of theory).

LC-MS (Method 2): R _t = 0.66min

MS (ES +): m / z = 421 (M-HCO ₂ H + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.08 (d, 3H), 2.31 (s, 3H), 2.53 (s, 3H), 3.28-3.43 (m, 2H), 4.17 (s, 1H ), 4.29 (s, 1H), 5.29 (s, 2H), 6.93 (s, 1H), 7.24 (quin., 2H), 7.54-7.65 (m, 1H), 7.74 (t, 1H), 8.19 (s 1H), 8.47 (s, 1H).

Example 283 Enantio-N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

Under argon, 14.8 mg (0.02 mmol) of activated carbon, palladium (II) hydroxide (20%) was added to 148 mg (0.21 mmol, purity 95%). 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-fluoro-2 -Methylprop-2-yl} carbamate benzyl trifluoroacetate (mirror isomer A) in 9 ml of ethanol, and the reaction mixture was hydrogenated under standard pressure for 5.5 h. The mixture was then filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was then concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The collected product fractions were treated in dichloromethane and a little methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The combined organic phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 61 mg of the target compound (68% of theory).

LC-MS (Method 2): R _t = 0.61min

MS (ES +): m / z = 421 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.01-1.06 (m, 3H), 1.67 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H; overlap with solvent peaks ), 3.24-3.39 (m, 2H; overlap with water peaks), 4.07-4.15 (m, 1H), 4.19-4.27 (m, 1H), 5.29 (s, 2H), 6.92 (s, 1H), 7.20- 7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.68 (t, 1H), 8.47 (s, 1H).

Example 284 Enantio-N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

20 mg (0.03 mmol) of activated carbon on palladium hydroxide under argon (II) (20%) was added to 201 mg (0.29 mmol, 95% purity) of the enantiomer from Example 304A- {1-[({8-[(2,6-difluorobenzyl) oxy] -2, 6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamic acid benzyl ester trifluoroacetate ( Mirror isomer B) in 9 ml of ethanol solution, and the reaction mixture was hydrogenated under standard pressure for 4 h. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was then concentrated. The residue was treated in acetonitrile / water, TFA was added and the mixture was purified twice by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The collected product was concentrated and the fractions were concentrated. The residue was treated in dichloromethane and a little methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 69 mg of the target compound (59% of theory).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 421 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.01-1.07 (m, 3H), 1.64 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H; overlap with solvent peaks ), 3.24-3.39 (m, 2H; overlapping with water peaks), 4.08-4.15 (m, 1H), 4.20-4.27 (m, 1H), 5.29 (s, 2H), 6.92 (s, 1H), 7.20- 7.28 (m, 2H), 7.55-7.64 (m, 1H), 7.66 (t, 1H), 8.47 (s, 1H).

Example 285 Enantiomer-N- (2-amino-3-fluoro-2-methylpropyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

15 mg (0.02 mmol) of activated carbon over palladium hydroxide under argon (II) (20%) was added to 170 mg (0.21 mmol, 87% purity) of the enantiomer from Example 305A- {1-[({2,6-dimethyl-8-[(2,3,6-tri Fluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamic acid benzyl ester trifluoroacetic acid The salt (mirromeric isomer A) was dissolved in 9 ml of ethanol, and the reaction mixture was hydrogenated under standard pressure for 5.5 hours. The mixture was then filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was then concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The collected fractions were treated with dichloromethane and a little methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 68 mg of the target compound (71% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 439 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.00-1.07 (m, 3H), 1.67 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H; overlap with solvent peaks ), 3.24-3.39 (m, 2H; overlap with water peaks), 4.08-4.15 (m, 1H), 4.20-4.27 (m, 1H), 5.34 (s, 2H), 6.92 (s, 1H), 7.25- 7.34 (m, 1H), 7.62-7.73 (m, 2H), 8.48 (s, 1H).

Example 286 Enantiomer-N- (2-amino-3-fluoro-2-methylpropyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

Under argon, add 20 mg (0.03 mmol) of palladium (II) hydroxide (20%) on activated carbon to 202 mg (0.28 mmol) of the enantiomer from Example 306A- {1-[({2,6- 二methyl -8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-fluoro-2-methylpropane- 2-yl} benzyl carbamate trifluoroacetate (mirror isomer B) in 9.1 ml of an ethanol solution, and the reaction mixture was hydrogenated under standard pressure for 2 h. The mixture was then filtered through a Millipore filter, and the filtrate was concentrated and dried under high vacuum. The residue was treated in acetonitrile / water, TFA was added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The collected product fractions were treated in dichloromethane and a little methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 82 mg of the target compound (66% of theory).

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 439 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.01-1.06 (m, 3H), 1.65 (br.s, 2H), 2.31 (s, 3H), 2.53 (s, 3H; overlap with solvent peaks ), 3.24-3.39 (m, 2H, overlapping with water peaks), 4.08-4.14 (m, 1H), 4.19-4.27 (m, 1H), 5.34 (s, 2H), 6.92 (s, 1H), 7.25- 7.34 (m, 1H), 7.62-7.73 (m, 2H), 8.48 (s, 1H).

Example 287 Enantiomer-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamidate (mirror isomer A)

Under argon, 17 mg of 10% palladium on carbon was added to 122 mg (0.21 mmol) of the enantiomer from Example 311A- {1-[({8-[(2,6-difluorobenzyl) oxy]]- 6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester ( Mirror isomers A) in 2 ml of DMF solution, and the mixture was hydrogenated at RT and standard pressure for 2 h. The reaction mixture was filtered through celite, the filter cake was washed with DMF and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (mobile phase: dichloromethane / 7N ammonia methanol solution = 1/0 to 30/1). The product was concentrated and the fractions were concentrated. The residue was repurified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.05% formic acid). The product fractions were concentrated and the residue was dried under high vacuum. This gave 47 mg of the target compound (44% of theory).

LC-MS (Method 2): R _t = 0.75min

MS (ES +): m / z = 453 (M-HCO ₂ H + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.91 (t, 3H), 1.12 (s, 3H), 1.43-1.60 (m, 2H), 2.58 (s, 3H), 3.30-3.46 (m , 2H; overlap with water peaks), 5.37 (s, 2H), 7.03-7.34 (m, 4H), 7.55-7.65 (m, 1H), 8.11 (br.s, 1H), 8.29 (s, 1H), 8.97 (s, 1H).

Example 288 Enantiomer-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

16.6 mg (0.03 mmol) of the enantiomer-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -6- ( Difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxamidine formate was treated in dichloromethane and a little methanol, and the mixture was treated with a saturated aqueous sodium hydrogen carbonate solution Wash twice. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. This gave 13 mg of the target compound (85% of theory).

LC-MS (Method 2): R _t = 0.79min

MS (ES +): m / z = 453 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.98 (s, 3H), 1.29-1.43 (m, 2H), 1.58 (br.s, 2H), 2.57 (s , 3H), 3.22 (q, 2H), 5.37 (s, 2H), 7.02-7.33 (m, 4H), 7.55-7.65 (m, 1H), 7.79 (br.s, 1H), 8.99 (s, 1H ).

Example 289 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamidate (mirror isomer B)

Under argon, 16 mg of 10% palladium on carbon was added to 121 mg (0.20 mmol) of the enantiomer from Example 312A- {1-[({8-[(2,6-difluorobenzyl) oxy]]- 6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester ( Mirror isomer B) in 2 ml of DMF solution, and the mixture was hydrogenated at RT and standard pressure for 2 hours. The mixture was then filtered through diatomaceous earth, the filter cake was washed with DMF and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (mobile phase: dichloromethane / 7N ammonia methanol solution = 1/0 to 30/1). The product was concentrated and the fractions were concentrated. The residue was repurified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.05% formic acid). The product fractions were concentrated and the residue was dried under high vacuum. This gave 49 mg of the target compound (46% of theory).

LC-MS (Method 2): R _t = 0.77min

MS (ES +): m / z = 467 (M-HCO ₂ H + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.89 (t, 3H), 1.13 (s, 3H), 1.29-1.55 (m, 4H), 2.58 (s, 3H), 3.30-3.45 (m , 2H; overlap with water peaks), 5.37 (s, 2H), 7.02-7.35 (m, 4H), 7.55-7.66 (m, 1H), 8,17 (br.s., 1H), 8.33 (s, 1H), 8.96 (s, 1H).

Example 290 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

17 mg (0.03 mmol) of the enantiomer-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6- (di Fluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxamidine formate was treated in dichloromethane and a little methanol, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. Twice. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. This gave 15 mg of the target compound (96% of theory).

LC-MS (Method 2): R _t = 0.83min

MS (ES +): m / z = 467 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.99 (s, 3H), 1.25-1.41 (m, 4H), 1.51 (br.s, 2H), 2.57 (s , 3H), 3.22 (q, 2H), 5.37 (s, 2H), 7.02-7.33 (m, 4H), 7.55-7.65 (m, 1H), 7.80 (br.s, 1H), 8.98 (s, 1H ).

Example 291 Enantiomer-N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2 -A Imidazolo [1,2-a] pyridine-3-carboxamidine (mirror isomer A)

Under argon, 7.4 mg (0.01 mmol) of activated carbon palladium (II) hydroxide (20%) was added to 74.6 mg (0.11 mmol) of the enantiomer from Example 313A- {1-[({8- [ (2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3- Fluoro-2-methylprop-2-yl} carbamate benzyl trifluoroacetate (mirror isomer A) in 4.5 ml of an ethanol solution, and the mixture was hydrogenated under standard pressure for 4 hours. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was then concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 16 mg of the target compound (31% of theory).

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 457 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 1.02-1.06 (m, 3H), 1.68 (br.s, 2H), 2.57 (s, 3H), 3.30-3.40 (m, 2H, partly The peaks of the water are hidden), 4.10-4.16 (m, 1H), 4.20-4.26 (m, 1H), 5.37 (s, 2H), 7.05-7.31 (m, 4H), 7.56-7.63 (m, 1H), 7.84 (t, 1H), 8.98 (s, 1H).

Example 292 Enantiomer-N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2 -A Imidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer B)

Under argon, add 4.2 mg (0.01 mmol) of palladium (II) hydroxide (20%) on activated carbon to 47 mg (0.06 mmol, 89% purity) of the enantiomer from Example 314A- {1-[({ 8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -3-fluoro-2-methylprop-2-yl} carbamate benzyl trifluoroacetate (mirror isomer B) in 2 ml of an ethanol solution, and the mixture was hydrogenated under standard pressure for 5 hours. The mixture was then filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was then concentrated. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was treated in dichloromethane and a little methanol and separated by thin layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 15: 1). The product fractions were concentrated and lyophilized. This gave 16 mg of the target compound (56% of theory).

LC-MS (Method 2): R _t = 0.75min

MS (ES +): m / z = 457 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 1.02-1.06 (m, 3H), 1.71 (br.s, 2H), 2.57 (s, 3H), 3.30-3.40 (m, 2H, part Concealed by water peaks), 4.10-4.16 (m, 1H), 4.20-4.26 (m, 1H), 5.37 (s, 2H), 7.05-7.31 (m, 4H), 7.56-7.63 (m, 1H), 7.84 (t, 1H), 8.98 (s, 1H).

Example 293 Racemic-N- (2-amino-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1 , 2-a] pyridine-3-carboxamide

250 mg (0.71 mmol) of 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxylate from Example 265A The acid, 298 mg (0.79 mmol) of HATU and 0.37 ml (2.14 mmol) of N, N-diisopropylethylamine were stirred in 4.8 ml of DMF for 20 min. At 0 ° C, 103 mg (0.86 mmol, 97% purity) of racemic 2-methylpentan-1,2-diamine was then added, and the mixture was stirred at 0 ° C for 30 min. Acetonitrile / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed once with a saturated aqueous sodium bicarbonate solution. The aqueous phase was washed twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 222 mg of the target compound (69% of theory).

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 449 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): 0.87 (t, 3H), 0.99 (s, 3H), 1.22-1.43 (m, 4H), 1.60 (br.s, 2H), 2.30 (s, 3H ), 2.55 (s, 3H), 3.14-3.28 (m, 2H), 5.32 (s, 2H), 6.91 (s, 1H), 7.25-7.33 (m, 1H), 7.59-7.73 (m, 2H), 8.48 (s, 1H).

Example 294 N ⁶ -({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) -L-ion Methyl urethane

75 mg (0.11 mmol) of N ^2- (third butoxycarbonyl) -N ⁶ -({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl) from Example 315A -Imidazo [1,2-a] pyridin-3-yl} carbonyl) -L-lysine methyl trifluoroacetate was first put into 0.54 ml of diethyl ether, and 0.54 ml (1.08 mmol) of 2N hydrochloric acid was added Ether solution and stir the mixture at room temperature overnight. The reaction solution was concentrated and the residue was dissolved in dichloromethane and washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by thick layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 20/1). This gave 22 mg of the target compound (42% of theory).

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 475 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.31-1.42 (m, 2H), 1.43-1.65 (m, 4H), 1.66-1.81 (m, 2H), 2.30 (s, 3H), 2.47 (s, 3H), 3.25-3.29 (m, 2H), 3.60 (s, 3H), 5.28 (s, 2H), 6.87-6.91 (m, 1H), 7.19-7.27 (m, 2H), 7.54-7.64 (m, 1H), 7.82 (t, 1H), 8.42 (s, 1H).

Example 295 Enantio-N- (2-amino-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1, 2-a] pyridine-3-carboxamide

215 mg of racemic-N- (2-amino-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy from Example 293 Group] imidazo [1,2-a] pyridine-3-carboxamide is separated into the mirror isomers by preparative separation on the palm phase [column: Daicel Chiralcel OZ-H, 5μm, 250 × 20mm, Mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 17ml / min; temperature: 40 ° C, detection: 210nm].

Mirror isomer A: Yield: 83 mg (> 99% ee)

R _t = 11.59min [Daicel Chiralcel OZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1ml / min; temperature: 40 ° C; detection: 235nm].

Example 296 Racemic-N- [2-amino-3- (4-fluorophenyl) -2-methylpropyl] -8-[(2,6-difluorobenzyl) oxy] -2,6 -Dimethylimidazo [1,2-a] pyridine-3-carboxamide

106 mg (0.32 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 134 mg (0.35 mmol) of HATU and 0.28 ml (1.60 mmol) of N, N-diisopropylethylamine were first put into 2 ml of DMF and stirred for 20 min. At 0 ° C, then 70 mg (0.38 mmol) of racemic 3- (4-fluoro) from Example 317A was added. Phenyl) -2-methylpropan-1,2-diamine, and the mixture was stirred at 0 ° C for 45 min. Acetonitrile / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were combined and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered and the filtrate was concentrated and lyophilized. This gave 121 mg of the target compound (75% of theory).

LC-MS (Method 2): R _t = 0.71min

MS (ES +): m / z = 497 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.94 (s, 3H), 2.31 (s, 3H), 2.55 (br.s., 3H), 2.63-2.69 (m, 2H), 3.17- 3.25 (m, 1H), 3.27-3.30 (m, 1H), 5.29 (s, 2H), 6.90-6.94 (m, 1H), 7.07-7.15 (m, 2H), 7.19-7.32 (m, 4H), 7.54-7.63 (m, 1H), 7.67 (t, 1H), 8.46-8.51 (m, 1H).

Example 297 Racemic-N- [2-amino-2-methyl-3- (pyridin-2-yl) propyl] -8-[(2,6-difluorobenzyl) oxy] -2,6 -Dimethylimidazo [1,2-a] pyridine-3-carboxamide

174 mg (0.52 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 219 mg (0.58 mmol) of HATU and 0.46 ml (2.62 mmol) of N, N-diisopropylethylamine were first put into 3.3 ml of DMF and stirred for 20 min. At 0 ° C, 1.15 g (0.63 mmol, estimated purity about 15%) of racemic 2-methyl-3- (pyridin-2-yl) propan-1,2-diamine tri from Example 319A was then added. Hydrochloride, and mix the mixture in Stir at RT overnight. Acetonitrile / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered and the filtrate was concentrated and lyophilized. This gave 106 mg of the target compound (42% of theory).

LC-MS (Method 2): R _t = 0.70min

MS (ES +): m / z = 480 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.01 (s, 3H), 1.67-2.12 (br.s, 2H), 2.31 (s, 3H), 2.60 (s, 3H), 2.84 (s , 2H), 3.23 (d, 2H), 5.29 (s, 2H), 6.93 (s, 1H), 7.19-7.28 (m, 3H), 7.32 (d, 1H), 7.54-7.64 (m, 1H), 7.69-7.79 (m, 2H), 8.51 (d, 1H), 8.57 (s, 1H).

Example 298 Enantiomer-N- [2-amino-2-methyl-3- (pyridin-2-yl) propyl] -8-[(2,6-difluorobenzyl) oxy] -2,6- Dimethylimidazo [1,2-a] pyridine-3-carboxamide (Mirror image isomer A)

106 mg of racemic-N- [2-amino-2-methyl-3- (pyridin-2-yl) propyl] -8-[(2,6-difluorobenzyl) oxy from Example 297 Group] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamidine is separated into mirror isomers by preparative separation on the opposite palm phase [column: Daicel Chiralpak ID, 5μm, 250 × 20mm, mobile phase: 70% methyl tert-butyl ether, 30% acetonitrile + 0.2% diethylamine, flow rate: 15ml / min; temperature: 40 ° C, detection: 220nm].

Mirror isomer A: Yield: 27 mg (98% ee)

R _t = 11.80min [Daicel Chiralcel ID, 5μm, 250 × 4.6mm; mobile phase: 70% methyl tert-butyl ether, 30% acetonitrile + 0.2% diethylamine; flow rate 1ml / min; temperature: 40 ° C; Detection: 235nm].

Example 299 Racemic-8-[(2,6-difluorobenzyl) oxy] -N- (3,3-difluoropiperidin-4-yl) -2,6-dimethylimidazo [1, 2-a] pyridine-3-carboxamide

81 mg (0.15 mmol) of racemic-4-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] -3,3-difluoropiperidine-1-carboxylic acid third butyl ester was first placed in 0.8 ml of diethyl ether, and 0.74 ml (1.47 mmol) of 2N hydrochloric acid was added Ether solution and stir the mixture at room temperature overnight. The mixture was then concentrated, dichloromethane and a drop of methanol were added to the residue and the mixture was washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 18 mg of the target compound (26% of theory).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 451 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.18-1.31 (m, 1H), 1.80-2.02 (m, 2H), 2.31 (s, 3H), 2.48 (s, 3H), 2.87-2.98 (m, 1H), 3.09-3.18 (m, 1H), 3.21-3.28 (m, 1H), 3.45-3.56 (m, 1H), 4.58-4.76 (m, 1H), 5.29 (s, 2H), 6.92 -6.95 (m, 1H), 7.20-7.28 (m, 2H), 7.55-7.64 (m, 1H), 8.20 (d, 1H), 8.25-8.31 (m, 1H).

Example 300 Enantiomer-N- (2-amino-2-methylbutyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1, 2-a] pyridine-3-carboxamide (mirror isomer A) hydrochloride

76 mg (0.18 mmol) of enantiomer-N- (2-amino-2-methylbutyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) from Example 274 (Yl) oxy] imidazo [1,2-a] pyridine-3-carboxamide is first put into 1.4 ml of ether, 0.11 ml (0.21 mmol) of 2N hydrochloric acid in ether is added and the mixture is stirred at RT for 30 min . The solvent was then distilled off and the residue was dried under high vacuum. This gave 86 mg of the target compound (99% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 435 (M-HCl + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 0.97 (s, 3H), 1.30-1.40 (m, 2H), 1.41-1.52 (m, 2H), 2.31 (s , 3H), 2.53 (s, 3H), 3.14-3.27 (m, 2H), 5.34 (s, 2H), 6.90-6.94 (m, 1H), 7.25-7.34 (m, 1H), 7.57-7.72 (m 2H), 8.49 (s, 1H).

Example 301 Racemic-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1 , 2-a] pyridine-3-carboxamide

75 mg (0.22 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridine-3-carboxylate from Example 325A Acid, 73 mg (0.23 mmol) of (benzotriazol-1-yloxy) bisdimethylaminomethylium fluoroborate and 0.14 ml (1.30 mmol) of 4-methylmorpholine were placed first In 0.8 ml of DMF, 45 mg (0.24 mmol) of racemic 2-methylpentan-1,2-diamine dihydrochloride from Example 326A was added and the mixture was stirred at RT overnight. A few drops of water and TFA were added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). The product fractions were concentrated and the residue was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted three times with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 68 mg of the target compound (69% of theory).

LC-MS (Method 2): R _t = 0.67min

MS (ES +): m / z = 445 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.83-0.91 (m, 3H), 1.04 (s, 3H), 1.22 (t, 3H), 1.28-1.41 (m, 4H), 2.31 (s , 3H), 2.91 (q, 2H), 3.18-3.30 (m, 2H), 5.29 (s, 2H), 6.92 (s, 1H), 7.25 (quin, 2H), 7.55-7.65 (m, 1H), 7.69-7.79 (m, 1H), 8.41 (s, 1H).

Example 302 Racemic-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- [2- (trifluoromethyl) piperidin-4-yl] imidazo [ 1,2-a] pyridine-3-carboxamide

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 94 mg (0.25 mmol) of HATU and 0.24 ml (1.35 mmol) of N, N-diisopropylethylamine were first put into 1.4 ml of DMF and stirred for 20 min. 55 mg (0.27 mmol) of racemic-2- (trifluoromethyl) piperidine-4-amine hydrochloride from Example 327A was then added and the mixture was stirred at RT overnight. The reaction solution was diluted with water / TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated under reduced pressure and then treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 65 mg of the target compound (60% of theory).

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 483 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.60-1.95 (m, 4H), 2.31 (s, 3H), 2.81-2.98 (m, 2H), 3.55-3.74 (m, 1H), 4.24 -4.33 (m, 1H), 5.29 (s, 2H), 6.92 (s, 1H), 7.24 (quin, 2H), 7.55-7.64 (m, 1H), 7.89 (d, 1H), 8.36 (s, 1H ).

Example 303 Racemic-N- (2-amino-2-methylpentyl) -8-[(2,3-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide

80 mg (0.19 mmol, purity 95%) of racemic- (1-{[(8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) from Example 330A Carbonyl] amino} -2-methylpent-2-yl) carbamic acid third butyl ester, 43 mg (0.21 mmol) of 2,3-difluorobenzyl bromide, 135 mg (0.41 mmol) of cesium carbonate and 3.1 mg (0.02 mmol) of potassium iodide was first placed in 3.6 ml of DMF and heated in a warm oil bath preheated to 60 ° C for 30 min. The reaction solution was concentrated and dried under high vacuum overnight. The residue was treated in ether, 0.94 ml (1.88 mmol) of a 2N solution of hydrochloric acid in ether was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 51 mg of the target compound (61% of theory).

LC-MS (Method 2): R _t = 0.67min

MS (ES +): m / z = 431 (M + H) ⁺

Example 304 Enantio-N- (2-amino-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1, 2-a] pyridine-3-carboxamide

215 mg of racemic-N- (2-amino-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy from Example 293 Group] imidazo [1,2-a] pyridine-3-carboxamide is separated into the mirror isomers by preparative separation on the palm phase [column: Daicel Chiralcel OZ-H, 5μm, 250 × 20mm, Mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 17ml / min; temperature: 40 ° C, detection: 210nm].

Mirror isomer B: Yield: 86 mg (97.5% ee)

R _t = 14.00min [Daicel Chiralcel OZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1ml / min; temperature: 40 ° C; detection: 235nm].

Example 305 Enantiomer-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6-methyl-2- (trifluoromethyl) imidazole Benzo [1,2-a] pyridine-3-carboxamide

46 mg (0.06 mmol) of the enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy]]-6-methyl-2- (trifluoromethyl) imidazole from Example 333A Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate was dissolved in 0.7 ml of ethanol and argon Add 4.4 mg (0.01 mmol) of 20% carbon palladium (II) hydroxide under air. The reaction mixture was Hydrogenated under quasi-pressure for 2 hours. The reaction mixture was adsorbed on diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 50/1). This gave 30 mg of the target compound (99% of theory).

LC-MS (Method 2): R _t = 0.91min

MS (ES +): m / z = 485 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.99 (s, 3H), 1.21-1.42 (m, 4H), 1.49-1.89 (m, 2H), 2.34 (s , 3H), 3.23 (s, 2H), 5.33 (s, 2H), 7.08 (s, 1H), 7.20-7.30 (m, 2H), 7.56-7.66 (m, 1H), 8.02 (s, 1H), 8.31-8.80 (m, 1H).

Example 306 Enantiomer-N- (2-amino-2-methylpentyl) -6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2 -a] pyridine-3-carboxamide

Under argon, 70 mg (0.09 mmol) of the enantiomer- {1-[({6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazole) from Example 292A Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl trifluoroacetate was first put into 1.9 ml of dichloromethane, 0.10 ml (0.14 mmol) of a 1N solution of boron tribromide in dichloromethane was added at 0 ° C under argon. The mixture was stirred at RT for 2.5 hours. Water was added to the reaction mixture, the mixture was concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product was dissolved in dichloromethane and washed with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated and the residue was Purified by preparative thin layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 20/1). The collected product was concentrated on a rotary evaporator. This gave 5 mg of the target compound (11% of theory).

LC-MS (Method 2): R _t = 0.84min

MS (ES +): m / z = 495 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 1.01 (s, 3H), 1.26-1.42 (m, 4H), 1.44-1.58 (m, 2H), 2.55 (s , 3H), 3.17-3.26 (m, 2H), 5.35 (s, 2H), 7.19-7.29 (m, 3H), 7.55-7.65 (m, 1H), 7.66-7.85 (m, 1H), 8.83 (d , 1H).

Example 307 N-[(1-aminocyclohexyl) methyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-carboxamide

163 mg (0.25 mmol) of (1-{[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2-a] from Example 334A Pyridine-3-yl} carbonyl) amino] methyl} cyclohexyl) carbamic acid third butyl trifluoroacetate was first put into 1.24 ml of diethyl ether, and 1.24 ml (2.48 mmol) of 2N hydrochloric acid in diethyl ether was added and The mixture was stirred at RT for 3 hours. An additional 0.5 ml (1 mmol) of 2N hydrochloric acid in diethyl ether was added, and the mixture was stirred at RT for 4 hours. The reaction mixture was concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phase was washed twice with dichloromethane, the combined organic phase was dried over sodium sulfate and filtered, and the residue was dried under high vacuum. This gave 89 mg of the target compound (81% of theory).

LC-MS (Method 2): R _t = 0.65min

MS (ES +): m / z = 443 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.19-1.48 (m, 8H), 1.49-1.61 (m, 2H), 1.62-1.77 (m, 2H), 2.31 (s, 3H), 2.53 (br.s., 3H), 3.24 (d, 2H), 5.28 (s, 2H), 6.92 (s, 1H), 7.18-7.29 (m, 2H), 7.54-7.66 (m, 2H), 8.49 ( s, 1H).

Example 308 N- (3-aminocyclopentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxyl Amidine (a mixture of stereoisomers)

119 mg (0.23 mmol) of {3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine from Example 335A -3-yl} carbonyl) amino] cyclopentyl} carbamic acid third butyl ester was first put into 1.2 ml of ether, 1.2 ml (2.31 mmol) of a 2N hydrochloric acid in ether solution was added and the mixture was stirred at RT overnight . The reaction mixture was concentrated, dichloromethane and a drop of methanol were added to the residue, and the mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane, and the combined organic phases were concentrated. This gave 93 mg of the target compound (92% of theory).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.37-1.50 (m, 2H), 1.67-1.83 (m, 2H), 1.87-2.02 (m, 2H), 2.31 (s, 3H), 2.49 (s, 3H), 3.36-3.42 (m, 1H), 4.30-4.40 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 1H), 8.12 (d, 1H), 8.53 (s, 1H).

Example 309 Enantio-N- (3-aminocyclopentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-carboxamide

85 mg of N- (3-aminocyclopentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a ] Pyridin-3-carboxamide is separated into isomeric isomers on the palm phase by preparative separation [column: Daicel Chiralcel AY-H, 5 μm, 250 × 20 mm, mobile phase: 50% isohexane, 50% Ethanol + 0.2% diethylamine, flow rate: 15ml / min; temperature: 25 ° C, detection: 220nm]. The product fractions were repurified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated.

Stereoisomer A: Yield: 15.7 mg (> 99% ee)

R _t = 4.82min [Daicel Chiralcel AY-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1ml / min; temperature: 40 ° C; detection: 220nm].

Example 310 Racemic-N- [2-amino-3- (1,3-benzothiazol-2-yl) -2-methylpropyl] -8-[(2,6-difluorobenzyl) oxy Yl] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

14 mg (0.04 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 18 mg (0.05 mmol) of HATU and 0.04 ml (0.21 mmol) of N, N-diisopropylethylamine were first put into 0.3 ml of DMF, the mixture was stirred for 20 min, and then 17 mg (0.07 mmol, Purity 94%) Racemic-3- (1,3-benzothiazol-2-yl) -2-methylpropan-1,2-diamine from Example 337A and the mixture was stirred at 0 ° C for 60 min. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated under reduced pressure, then the residue was dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution and the combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 16 mg of the target compound (68% of theory).

LC-MS (Method 2): R _t = 0.82min

MS (ES +): m / z = 536 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.11 (s, 3H), 1.18-1.29 (m, 2H), 2.31 (s, 3H), 2.58 (s, 3H), 3.16-3.27 (m , 2H), 3.38-3.45 (m, 2H), 5.29 (s, 2H), 6.90-6.95 (m, 1H), 7.20-7.29 (m, 2H), 7.37-7.43 (m, 1H), 7.44-7.50 (m, 1H), 7.54-7.64 (m, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 8.05 (d, 1H), 8.49 (s, 1H).

Example 311 Racemic-N- (2-amino-2-methylpentyl) -2,6-dimethyl-8-[(2,3,5,6-tetrafluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxamide

80 mg (0.19 mmol) of racemic- (1-{[((8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino) from Example 330A ) -2-methylpent-2-yl) carbamic acid third butyl ester, 50 mg (0.21 mmol) of 2,3,5,6-tetrafluorobenzyl bromide, 135 mg (0.41 mmol) of cesium carbonate and 3 mg ( 0.02 mmol) of potassium iodide was first put into 4 ml of DMF, and the mixture was heated in a warm oil bath preheated to 60 ° C. for 60 min. The reaction solution was concentrated and dried under high vacuum overnight. The residue was treated in 1 ml of ether, 0.94 ml (1.88 mmol) of a 2N solution of hydrochloric acid in ether was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 60 mg of the target compound (68% of theory).

LC-MS (Method 2): R _t = 0.73min

MS (ES +): m / z = 467 (M + H) ⁺

Example 312 Racemic-8-[(2,6-difluorobenzyl) oxy] -N- (5,5-difluoropiperidin-3-yl) -2,6-dimethylimidazo [1, 2-a] pyridine-3-carboxamide

89 mg (0.16 mmol) of racemic-5-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] -3,3-difluoropiperidine-1-carboxylic acid third butyl ester was first put into 0.8 ml of diethyl ether, and 0.78 ml (1.55 mmol) of 2N hydrochloric acid was added Ether solution and stir the mixture at RT overnight. The reaction mixture was concentrated, dichloromethane and a drop of methanol were added to the residue, and the mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 67 mg of the target compound (91% of theory).

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 451 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.22-1.28 (m, 1H), 1.99-2.18 (m, 1H), 2.31 (s, 3H), 2.38-2.45 (m, 1H), 2.48 (s, 3H), 2.57-2.64 (m, 1H), 2.82-2.98 (m, 1H), 3.01-3.18 (m, 2H), 4.12-4.23 (m, 1H), 5.28 (s, 2H), 6.91 -6.95 (m, 1H), 7.20-7.28 (m, 2H), 7.54-7.65 (m, 1H), 7.77 (d, 1H), 8.42 (s, 1H).

Example 313 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- [4- (trifluoromethyl) pyrrolidin-3-yl] imidazo [1,2- a) Pyridine-3-carboxamide (mixture of stereoisomers)

18 mg (0.03 mmol) of racemic 3-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] -4- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate (a mixture of stereoisomers) was first placed in 0.1 ml To diethyl ether, 0.13 ml (0.26 mmol) of a 2N hydrochloric acid in diethyl ether solution was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (mobile phase: dichloromethane / methanol = 20/1). This gave 5.8 mg of the target compound (45% of theory).

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 469 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): d [ppm] = 2.31 (s, 3H), 2.48 (s, 3H), 2.75-2.82 (m, 1H), 2.90-2.98 (m, 1H), 3.04-3.22 (m, 2H), 3.24-3.28 (m, 2H), 4.51-4.59 (m, 1H), 5.29 (s, 2H), 6.93 (s, 1H), 7.19-7.27 (m, 2H), 7.54-7.63 (m, 1H), 8.06 (d, 1H), 8.39 (s, 1H).

Example 314 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N-[(7S, 8aS) -2-methyloctahydropyrrolo [1,2-a] pyridine -7-yl] imidazo [1,2-a] pyridine-3-carboxamide

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 111 mg (0.29 mmol) of HATU and 0.20 ml (1.13 mmol) of N, N-diisopropylethylamine were first placed in 2 ml of DMF, the mixture was stirred for 10 min, and then 88 mg (0.29 mmol) of (7S, 8aS) -2-methyloctahydropyrrolo [1,2-a] pyridine -7-amine trihydrochloride dihydrate (commercially available, CAS registration number: 1268826-45-9) and the mixture was stirred at RT overnight. TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were combined, the solvent was concentrated and the residue was lyophilized. The residue was treated in dichloromethane and washed once with a saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated and lyophilized. This gave 81 mg of the target compound (75% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 470 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.36-1.49 (m, 1H), 1.84-2.05 (m, 1H), 2.06-2.28 (m, 5H), 2.30 (s, 3H), 2.45 (s, 3H), 2.72-2.84 (m, 1H), 2.86-3.00 (m, 3H), 4.40 (quin, 1H), 5.28 (s, 2H), 6.90 (s, 1H), 7.24 (quin, 2H ), 7.54-7.64 (m, 1H), 8.06 (d, 1H), 8.35 (s, 1H).

Example 315 Enantiomer-N- (1-amino-2-methylbut-2-yl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxamide

165 mg (0.24 mmol) of {2-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a ] Pyridin-3-yl} carbonyl) amino] -2-methylbutyl} carbamic acid benzyl ester was first placed in 2.5 ml of ethanol, and 17 mg (0.02 mmol) of 20% carbon was added under argon Palladium (II) hydroxide. The mixture was then hydrogenated at RT and standard pressure for 2.5 hours. The reaction mixture was adsorbed on diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). This gave 90 mg of the target compound (84% of theory).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 435 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 0.83 (t, 3H), 1.28 (s, 3H), 1.57-1.72 (m, 1H), 1.73-1.86 (m, 2H), 2.31 (s , 3H), 2.61 (d, 1H), 2.84 (d, 1H), 5.34 (s, 2H), 6.90 (d, 1H), 7.18 (s, 1H), 7.25-7.32 (m, 1H), 7.62- 7.71 (m, 1H), 8.49 (s, 1H).

Example 316 Racemic-N- (azetidin-3-yl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridin-3-carboxamide

Add 1.5 ml (3.00 mmol) of a 2N solution of hydrogen chloride in ether to 193 mg (0.30 mmol) of racemic 3-[({8-[(2,6-difluorobenzyl) oxy]] from Example 341A. 2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] azacycloheptane-1-carboxylic acid third butyl trifluoroacetate, and the mixture Stir at RT until overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was dissolved in dichloromethane and washed once with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated and lyophilized. This gave 114 mg of the target compound (89% of theory).

LC-MS (Method 2): R _t = 0.63min

MS (ES +): m / z = 429 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.43-1.74 (m, 5H), 1.78-1.88 (m, 1H), 2.31 (s, 3H), 2.48 (s, 3H), 2.66-2.73 (m, 1H), 2.77 (t, 2H), 2.92-2.99 (m, 1H), 3.98-4.08 (m, 1H), 5.28 (s, 2H), 6.90 (s, 1H), 7.20-7.28 (m , 2H), 7.55-7.68 (m, 2H), 8.45 (s, 1H).

Example 317 Racemic-N- (2-amino-2-methylpentyl) -8-[(2-fluoro-3-methylbenzyl) oxy] -2,6-dimethylimidazo [1 , 2-a] pyridine-3-carboxamide

90 mg (0.21 mmol) of racemic- (1-{[((8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino) from Example 330A ) -2-methylpent-2-yl) carbamate tert-butyl ester, 47 mg (0.23 mmol) of 2-fluoro-3-methylbenzyl bromide, 152 mg (0.46 mmol) of cesium carbonate, and 3.5 mg (0.02 mmol) of potassium iodide was first put into 4 ml of DMF, and the mixture was heated in a warm oil bath preheated to 60 ° C. for 30 min. The reaction solution was concentrated and dried under high vacuum overnight. The residue was treated in 1 ml of ether, 1.06 ml (2.11 mmol) of a 2N solution of hydrochloric acid in ether was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 48 mg of the target compound (53% of theory).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 427 (M + H) ⁺

Example 318 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridine -3-carboxamide

Under argon, 50 mg (0.07 mmol) of the enantiomer- {1-[({6-bromo-8-[(2,6-difluorobenzyl) oxy] -2-methylimidazole] from Example 292A [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester was first placed in 0.7 ml of ethanol, and 7 mg (0.01 mmol, 10%) of carbon on palladium and the mixture was hydrogenated at RT and standard pressure for 1 hour. The reaction mixture was transferred to diatomaceous earth and purified by silica gel chromatography (mobile phase dichloromethane / 2N ammonia methanol solution = 60/1). This gave 27 mg of the target compound (94% of theory).

LC-MS (Method 2): R _t = 0.61min

MS (ES +): m / z = 417 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 0.99 (s, 3H), 1.21-1.42 (m, 4H), 1.43-1.72 (m, 2H), 2.56 (s , 3H), 3.14-3.27 (m, 2H), 5.31 (s, 2H), 6.94 (t, 1H), 7.00 (d, 1H), 7.20-7.28 (m, 2H), 7.55-7.63 (m, 1H ), 7.64-7.69 (m, 1H), 8.64 (d, 1H).

Example 319 3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino]- L-alanine methyl ester

75 mg (0.14 mmol) of N- (third butoxycarbonyl) -3-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -L-alanine methyl ester was first put into 0.7 ml of ether, 0.67 ml (1.35 mmol) of 2N hydrochloric acid in ether and The mixture was stirred at RT overnight. The reaction solution was concentrated and the residue was dissolved in dichloromethane and washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 55 mg of the target compound (92% of theory).

LC-MS (Method 2): R _t = 0.63min

MS (ES +): m / z = 433 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.84-2.03 (m, 2H), 2.31 (s, 3H), 2.48 (s, 3H), 3.46-3.51 (m, 2H), 3.56-3.61 (m, 1H), 3.63 (s, 3H), 5.28 (s, 2H), 6.89-6.94 (m, 1H), 7.19-7.27 (m, 2H), 7.53-7.63 (m, 1H), 7.81 (t , 1H), 8.41-8.46 (m, 1H).

Example 320 Racemic-N- (2-amino-1,2-dimethylcyclopropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (racemate)

Add 0.94 ml of DMF and 1.26 ml (7.22 mmol) of N, N-diisopropylethylamine to 631 mg (2.41 mmol) of racemic-1,2-dimethylcyclopropane-1,2- Diamine dibromide (described in: WvdSaal et al. Liebigs Annalen der Chemie 1994, 569-580) and the mixture was heated to 60 ° C. 200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine from Example 21A was stirred in advance at RT for 10 min. -3-carboxylic acid, 0.21 ml (1.20 mmol) of N, N-diisopropylethylamine and 275 ml (0.72 mmol) of HATU in 2.8 ml of DMF were added dropwise to the reaction mixture, and the mixture was stirred at 60 ° C. for 30 min. Water and TFA were added to the mixture, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate, the filtrate was concentrated and the residue was concentrated. This gave 175 mg of the target compound (70% of theory).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) 69 = 0.54 (d, 1 H), 0.67 (d, 1 H), 1.32 (s, 3 H), 1.49 (s, 3 H), 1.79 (br.s , 2 H), 2.31 (s, 3 H), 5.29 (s, 2 H), 6.89 (s, 1 H), 7.23 (t, 2 H), 7.54-7.63 (m, 1 H), 7.85 (s , 1 H), 8.41-8.45 (m, 1 H), [additional signal is hidden under solvent peak].

Example 321 Racemic-N- {2-amino-2-methyl-3- [1- (5-methyl-1,2- Azole-3-yl) -1H-1,2,4-triazol-3-yl] propyl} -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Imidazo [1,2-a] pyridine-3-carboxamide

114 mg (0.34 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 143 mg (0.38 mmol) of HATU and 0.18 ml (1.03 mmol) of N, N-diisopropylethylamine were first put into 2.2 ml of DMF, the mixture was stirred for 20 min, and then 105 mg (0.44 mmol) was added at 0 ° C Racemic-2-methyl-3- [1- (5-methyl-1,2- Azol-3-yl) -1H-1,2,4-triazol-3-yl] propan-1,2-diamine and the mixture was stirred at 0 ° C for 60 min. The reaction mixture was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The concentrated product fractions were partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The aqueous phase was re-extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated and lyophilized. This gave 73 mg of the target compound (38% of theory).

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 551 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.11 (s, 3H), 1.32-1.46 (m, 1H), 2.30 (s, 3H), 2.49 (br.s., 3H), 2.57 ( s, 3H), 2.89 (s, 2H), 3.36-3.43 (m, 1H), 5.29 (s, 2H), 6.73-6.78 (m, 1H), 6.92 (s, 1H), 7.19-7.29 (m, 2H), 7.53-7.67 (m, 2H), 8.52 (s, 1H), 9.21 (s, 1H).

Example 322 Enantiomer-N- (2-amino-2-methylpentyl) -2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6-methylimidazo [1 , 2-a] pyridine-3-carboxamide

Under argon, 74 mg (0.10 mmol) of the enantiomer-{1-[({2-cyclopropyl-8-[(2,6-difluorobenzyl) oxy] -6] -formaldehyde from Example 357A) Imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate was first placed in 1 ml of ethanol, added 11 mg (0.01 mmol) of 10% palladium on carbon and the mixture was hydrogenated at RT and standard pressure for 1 hour. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was concentrated. The product was dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. From this To 41 mg of the target compound (82% of theory).

LC-MS (Method 2): R _t = 0.78min

MS (ES +): m / z = 457 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86 (t, 3H), 0.92-0.98 (m, 4H), 1.00 (s, 3H), 1.21-1.42 (m, 4H), 1.54-2.00 (br.s, 2H), 2.25-2.34 (m, 4H), 3.15-3.29 (m, 2H), 5.28 (s, 2H), 6.92 (s, 1H), 7.19-7.28 (m, 2H), 7.54 -7.64 (m, 1H), 7.75 (t, 1H), 8.54 (s, 1H).

Example 323 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6-ethyl-2-methylimidazo [1, 2-a] pyridine-3-carboxamide

25 mg (0.04 mmol, 76% purity) of the enantiomer of Example 359A- {1-[({8-[(2,6-difluorobenzyl) oxy] -6-ethynyl-2-methylimidazole Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester was dissolved in 0.5 ml of ethanol, and 2.3 was added under argon mg (0.002 mmol) of 10% palladium on carbon. The reaction mixture was then hydrogenated at RT and standard pressure for 2 hours. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was concentrated and dried under high vacuum. The residue was purified by preparative thin layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1). This gave 2.8 mg of the target compound (13% of theory, 92% purity).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 445 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 1.04 (s, 3H), 1.23 (t, 6H), 1.30-1.40 (m, 6H), 1.42-1.57 (m, 2H), 2.54 (s , 3H), 2.60-2.66 (m, 2H), 5.32 (s, 2H), 6.94-6.96 (m, 1H), 7.20-7.26 (m, 2H), 7.55-7.62 (m, 1H), 7.63-7.72 (m, 1H), 8.48-8.51 (m, 1H).

Example 324 N-[(1R, 3S) -3-amino-2,2,3-trimethylcyclopentyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide

75 mg (0.23 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 112 mg (0.29 mmol) of HATU and 0.20 ml (1.13 mmol) of N, N-diisopropylethylamine were first placed in 2.2 ml of DMF, the mixture was stirred for 10 min, and then 63 mg (0.29 mmol) of (1S, 3R) -1,2,2-trimethylcyclopentane-1,3-diamine dihydrochloride and the mixture was stirred at RT for one hour. TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and dried under high vacuum. The residue was treated in dichloromethane and washed once with a saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated. This gave 90 mg of the target compound (85% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 457 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.86-0.92 (m, 6H), 1.10 (s, 3H), 1.56- 1.66 (m, 1H), 1.70 (t, 2H), 2.07-2.17 (m, 1H), 2.31 (s, 3H), 2.53 (s, 3H), 4.18-4.27 (m, 1H), 5.28 (s, 2H), 6.92 (s, 1H), 7.20-7.28 (m, 2H ), 7.54-7.64 (m, 1H), 8.38 (d, 1H), 8.65 (s, 1H).

Example 325 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -N- [2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1, 5-naphthyridin-4-yl] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

50 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 69 mg (0.18 mmol) of HATU and 0.13 ml (0.75 mmol) of N, N-diisopropylethylamine were first placed in 1.5 ml of DMF, the mixture was stirred for 10 min, and then 51 mg (0.18 mmol) of Enantiomer-2-ethyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-amine hydrochloride of Example 361A and the mixture was stirred at RT 2.5 hours. Water was added to the reaction mixture, and the formed solid was filtered off and dried under high vacuum. This gave 66 mg of the target compound (76% of theory).

LC-MS (Method 2): R _t = 1.12min

MS (ES +): m / z = 560 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.99 (t, 3H), 1.48-1.72 (m, 3H), 2.32 (s, 3H), 2.36-2.44 (m, 1H), 2.57 (s , 3H), 3.49-3.59 (m, 1H), 5.20-5.27 (m, 1H), 5.29 (s, 2H), 6.70 (s, 1H), 6.93 (s, 1H), 7.02 (d, 1H), 7.20-7.29 (m, 2H), 7.43 (d, 1H), 7.54-7.65 (m, 1H), 8.09 (d, 1H), 8.50 (s, 1H).

Example 326 Enantiomer-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- [2-methyl-6- (trifluoromethyl) -1,2,3 , 4-tetrahydro-1,5-naphthyridin-4-yl] imidazo [1,2-a] pyridine-3-carboxamide

49 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 67 mg (0.18 mmol) of HATU and 0.13 ml (0.74 mmol) of N, N-diisopropylethylamine were first placed in 1.5 ml of DMF, and 47 mg (0.18 mmol) of the enantiomer from Example 363A was added at RT. 2-methyl-6- (trifluoromethyl) -1,2,3,4-tetrahydro-1,5-naphthyridin-4-amine hydrochloride and the mixture was stirred at RT for 3 hours. Water was added to the reaction mixture, and the formed solid was filtered off and dried under high vacuum. This gave 63 mg of the target compound (74% of theory).

LC-MS (Method 2): R _t = 1.06min

MS (ES +): m / z = 546 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.91-0.97 (m, 1H), 1.23 (d, 3H), 1.62-1.73 (m, 1H), 2.32 (s, 3H), 2.56 (br .s., 3H), 3.66-3.78 (m, 1H), 5.20-5.27 (m, 1H), 5.29 (s, 2H), 6.76-6.82 (m, 1H), 6.90-6.99 (m, 2H), 7.19-7.29 (m, 2H), 7.43 (d, 1H), 7.55-7.64 (m, 1H), 8.07-8.13 (m, 1H), 8.48 (s, 1H).

Example 327 Enantio-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -6-methyl-2-propylimidazo [1, 2-a] pyridine-3-carboxamide

Under argon, 107 mg (0.18 mmol) of the enantiomer-{1-[({8-[(2,6-difluorobenzyl) oxy]]-6-methyl-2-propyl from Example 366A Imidazo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylbut-2-yl} carbamic acid benzyl ester was first placed in 3 ml of DMF, and 15 mg of 10% activity was added Palladium on carbon and the mixture was hydrogenated at RT and standard pressure for 2 hours. The reaction mixture was filtered through celite, the filter cake was thoroughly washed with DMF and the filtrate was concentrated. The residue was treated in ethanol and filtered through celite again and concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (mobile phase: dichloromethane / 7N ammonia methanol solution: 1/0 to 5/1). This gave 77 mg of the target compound (93% of theory).

LC-MS (Method 2): R _t = 0.71min

MS (ES +): m / z = 445 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.82-0.93 (m, 6H), 1.00 (s, 3H), 1.31-1.45 (m, 2H), 1.60-1.72 (m, 2H), 2.30 (s, 3H), 2.86 (t, 2H), 3.15-3.28 (m, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.24 (t, 2H), 7.55-7.64 (m, 1H ), 7.70 (t, 1H), 8.41 (s, 1H).

Example 328 Enantio-N- (2-aminocyclobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-Carboxamide (Mirror Isomer A)

77 mg (0.15 mmol) of the enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] cyclobutyl} carbamic acid third butyl ester (mirror isomer A) was first placed in 0.8 ml of diethyl ether, 0.77 ml (1.54 mmol) of 2N hydrochloric acid and Ether and the mixture was stirred at RT overnight. The reaction solution was concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 56 mg of the target compound (89% of theory).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 401 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.32-1.45 (m, 1H), 1.47-1.59 (m, 1H), 1.92-2.03 (m, 2H), 2.31 (s, 3H), 2.49 (br.s., 3H), 3.25-3.30 (m, 1H), 4.00-4.11 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.64 (m, 1H), 8.00 (d, 1H), 8.41 (s, 1H).

Example 329 Enantio-N- (2-aminocyclobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-Carboxamide (Mirror Isomer B)

67 mg (0.13 mmol) of the enantiomer- {2-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] cyclobutyl} carbamic acid third butyl ester (mirror isomer B) was first placed in 0.7 ml of ether, and 0.67 ml (1.34 mmol) of 2N hydrochloric acid Ether solution and the mixture was stirred at RT overnight. The reaction solution was concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 51 mg of the target compound (94% of theory).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 401 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.32-1.45 (m, 1H), 1.47-1.59 (m, 1H), 1.92-2.03 (m, 2H), 2.31 (s, 3H), 2.49 (br.s., 3H), 3.25-3.30 (m, 1H), 4.00-4.11 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.64 (m, 1H), 8.00 (d, 1H), 8.41 (s, 1H).

Example 330 Racemic-N- (2-aminocyclopropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine -3-carboxamide

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 206 mg (0.54 mmol) of HATU and 0.47 ml (2.71 mmol) of N, N-diisopropylethylamine were first put into 1.34 ml of DMF, and the mixture was stirred at RT for 10 min. The reaction mixture was slowly added dropwise to a solution of 0.54 ml (1.13 mmol) of racemic-cyclopropane-1,2-diamine hydrochloride in 0.45 ml of DMF, and the mixture was stirred at RT overnight. TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was purified by thin layer chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 10/1). This gave 18 mg of the target compound (10% of theory).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 387 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.66-0.72 (m, 1H), 0.73-0.79 (m, 1H), 1.85-1.95 (m, 2H), 2.31 (s, 3H), 2.33 -2.36 (m, 1H), 2.40 (s, 3H), 2.60-2.66 (m, 1H), 5.27 (s, 2H), 6.90 (s, 1H), 7.19-7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.82 (d, 1H), 8.40 (s, 1H).

Example 331 Racemic-N- (2-amino-2-methylcyclobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1, 2-a] pyridine-3-carboxamide

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 206 mg (0.54 mmol) of HATU and 0.47 ml (2.71 mmol) of N, N-diisopropylethylamine were first put into 1.34 ml of DMF, and the mixture was stirred at RT for 10 min. The reaction mixture was slowly added dropwise to 0.54 ml (1.81 mmol) of racemic-1-methylcyclobutane-1,2-diamine dihydrochloride (described in: K.-H. Scholz; J. Hinz; H.-G. Heine; W. Hartmann, Liebigs Annalen der Chemie, 1981, 248-255; Duschinsky; Dolan Journal of the American Chemical Society, 1945, 67, 2079, 2082), The mixture was stirred at RT until overnight. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The concentrated fraction was treated with dichloromethane and a little methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 100 mg of the target compound (52% of theory).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.12 (s, 3H), 1.57-1.73 (m, 3H), 1.88-1.97 (m, 1H), 1.98-2.07 (m, 2H), 2.31 (s, 3H), 2.51 (br.s., 3H), 4.20 (q, 1H), 5.28 (s, 2H), 6.90 (s, 1H), 7.19-7.28 (m, 2H), 7.54-7.64 ( m, 1H), 7.76 (d, 1H), 8.38 (s, 1H).

Example 332 Enantio-N- [2-amino-2-methylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer A)

95 mg of racemic-N- [2-amino-2-methylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyli-imidazole Benzene- [1,2-a] pyridine-3-carboxamide (Example 331) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 × 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate 20ml / min; temperature: 20 ° C, detection: 250nm].

Mirror isomer A: 29mg (> 99% ee)

R _t = 9.47min [Daicel Chiralcel OZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 30 ° C; detection : 220nm].

LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 1.12 (s, 3 H), 1.55-1.75 (m, 3 H), 1.85-2.01 (m, 1 H), 2.31 (s, 3 H), 4.21 (q, 1 H), 5.28 (s, 2 H), 6.90 (s, 1 H), 7.24 (t, 2 H), 7.54-7.64 (m, 1 H), 7.77 (d, 1 H), 8.38 (s, 1 H).

Example 333 Enantio-N- [2-amino-2-methylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide (mirror isomer B)

95 mg of racemic-N- [2-amino-2-methylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyli-imidazole Benzene- [1,2-a] pyridine-3-carboxamide (Example 331) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 × 20 mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate 20ml / min; temperature: 20 ° C, detection: 250nm].

Mirror isomer B: 32mg (purity 90%,> 83% ee)

R _t = 15.21min [Daicel Chiralcel OZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 30 ° C; detection : 220nm].

LC-MS (Method 2): R _t = 0.55min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) 69 = 1.12 (s, 3 H), 1.55-1.75 (m, 3 H), 1.85-2.00 (m, 1 H), 2.31 (s, 3 H), 4.21 (q, 1 H), 5.28 (s, 2 H), 6.90 (s, 1 H), 7.24 (t, 2 H), 7.54-7.64 (m, 1 H), 7.77 (d, 1 H), 8.38 (s, 1 H).

Example 334 N- (3-aminocyclobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxyl Amidine (cis / trans mixture)

Add 0.75 ml of DMF, 0.94 ml (5.42 mmol) of N, N-diisopropylethylamine and 0.75 ml of DMSO to 287 mg (1.81 mmol) of cyclobutane-1,3-diamine dihydrochloride (Cis / trans mixture) and the mixture was stirred at RT for one hour. The suspension was heated to 60 ° C. 0.75 ml of DMSO was added, and then 150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazolide from Example 21A was stirred beforehand at RT for 10 min [1,2-a] pyridine-3-carboxylic acid, 0.16 ml (0.90 mmol) of N, N-diisopropylethylamine and 206 mg (0.54 mmol) of HATU in 1.3 ml of a DMF solution. The mixture was stirred at 60 ° C for 30 min, then water and TFA were added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate, the filtrate was concentrated and the residue was concentrated. This gave 110 mg of the target compound (60% of theory).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 401 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 1.66-1.82 (m, 3 H), 1.94-2.06 and 2.19-2.27 (m, 1 H), 2.30 (s, 3 H), 2.47 (s, 3 H), 2.97-3.08 and 3.91-4.03 (m, 1 H), 5.28 (s, 2 H), 6.90 (s, 1 H), 7.24 (t, 2 H), 7.52-7.64 (m, 1 H) , 7.92 and 8.08 (d and d, 1 H), 8.35-8.40 (m, 1 H).

Example 335 Racemic-N- [2-amino-1,2-dimethylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

Add 1 ml of DMF, 1.26 ml (7.22 mmol) of N, N-diisopropylethylamine and 2 ml of DMSO to 451 mg (2.41 mmol) of racemic-1,2-dimethylcyclobutane-1 In 2-diamine dihydrochloride (described in: K.-H. Scholz; J. Hinz; H.-G. Heine; W. Hartmann, Liebigs Annalen der Chemie, 1981, 248-255; JLGagnon; WW Zajac, Synthetic Commununications 1996, 26, 837-846), and the mixture was stirred at 60 ° C. 200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a from Example 21A was added dropwise before stirring at RT for 10 min. ] A 1.8 ml DMF solution of pyridine-3-carboxylic acid, 0.21 ml (1.20 mmol) of N, N-diisopropylethylamine and 275 mg (0.72 mmol) of HATU. The solution was stirred at 60 ° C for 30 min, then water and TFA were added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the organic phase was dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was concentrated. This gave 198 mg of the target compound (77% of theory).

LC-MS (Method 2): R _t = 0.64min

MS (ES +): m / z = 429 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) 69 = 1.23 (s, 3 H), 1.45 (s, 3 H), 1.60-1.76 (m, 3 H), 1.93-2.04 (m, 1 H), 2.31 (s, 3 H), 2.47 (s, 3 H), 5.29 (s, 2 H), 6.88 (s, 1 H), 7.22 (t, 2 H), 7.54-7.63 (m, 1 H), 7.80 (s, 1 H), 8.36 (s, 1 H).

Example 336 Enantiomer-N-[(2-amino-1,2-dimethylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

190 mg of racemic-N- [2-amino-1,2-dimethylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Imidazolo [1,2-a] pyridine-3-carboxamide (Example 335) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 × 20 mm, mobile phase : 45% isopropanol, 50% isohexane, 5% + isopropanol + 2% diethylamine, flow rate 20ml / min; temperature: 25 ° C, detection: 210nm].

Mirror isomer A: 20mg (> 99% ee)

R _t = 6.26min [Daicel Chiralcel OZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; 30 ° C; detection : 220nm].

LC-MS (Method 2): R _t = 0.59min

MS (ES +): m / z = 429 (M + H) ⁺

¹ H NMR (500MHz, DMSO-d ₆ ) δ = 1.25 (s, 3 H), 1.48 (s, 3 H), 1.63-1.82 (m, 3 H), 1.93-2.04 (m, 1 H), 2.31 (s, 3 H), 2.49 (s, 3 H), 5.29 (s, 2 H), 6.89 (s, 1 H), 7.23 (t, 2 H), 7.54-7.63 (m, 1 H), 7.81 (s, 1 H), 8.37 (s, 1 H).

Example 337 Enantiomer-N-[(2-amino-1,2-dimethylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

190 mg of racemic-N-[(1S, 2S) -2-amino-1,2-dimethylcyclobutyl] -8-[(2,6-difluorobenzyl) oxy]- 2,6-Dimethylimidazo [1,2-a] pyridine-3-carboxamide (Example 335) was separated into mirror isomers on the opposite palm phase [column: Daicel Chiralcel OZ-H, 5 μm, 250 × 20mm, mobile phase: 45% isopropanol, 50% isohexane, 5% + isopropanol + 2% diethylamine, flow rate 20ml / min; temperature: 25 ° C, detection: 210nm].

Mirror isomer B: 16mg (> 99% ee)

R _t = 13.44min [Daicel Chiralcel OZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% isopropanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 30 ° C; Detection: 220nm].

LC-MS (Method 2): R _t = 0.59min

MS (ES +): m / z = 429 (M + H) ⁺

¹ H NMR (500MHz, DMSO-d ₆ ) δ = 1.26 (s, 3 H), 1.48 (s, 3 H), 1.61-1.78 (m, 3 H), 1.93-2.04 (m, 1 H), 2.31 (s, 3 H), 2.49 (s, 3 H), 5.29 (s, 2 H), 6.89 (s, 1 H), 7.23 (t, 2 H), 7.54-7.63 (m, 1 H), 7.81 (s, 1 H), 8.36 (s, 1 H).

Example 338 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1,2-a] pyridine-3-carboxamide

180 mg (0.26 mmol) of the enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] -2-ethyl-6-methylimidazo [1, 2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate was dissolved in 2.8 ml of ethanol, and 18.2 was added under argon mg (0.03 mmol) of palladium (II) hydroxide on 20% carbon. The reaction mixture was then hydrogenated at RT and standard pressure for two hours. The reaction mixture was transferred to diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 50/1). This gave 94 mg of the target compound (81% of theory).

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 445 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 0.99 (s, 3H), 1.22 (t, 3H), 1.26-1.40 (m, 4H), 1.41-1.54 (m , 2H), 2.30 (s, 3H), 2.91 (q, 2H), 3.14-3.25 (m, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.71 (m, 2H), 8.41 (s, 1H).

Example 339 Racemic-8-[(2,6-difluorobenzyl) oxy] -N- (6-methoxy-1,2,3,4-tetrahydroquinolin-4-yl) -2, 6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 126 mg (0.33 mmol) of HATU and 117 mg (0.90 mmol) of N, N-diisopropylethylamine were first placed in 1 ml of DMF, and the mixture was stirred at RT for 10 min. Then 62 mg (0.35 mmol) of racemic-6-methoxy-1,2,3,4-tetrahydroquinoline-4-amine was added and the mixture was stirred at RT for 1 h. Acetonitrile, TFA, and water were added to the reaction mixture, and the product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated. This gave 129 mg (87% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.82min

MS (ES +): m / z = 493 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.89-2.10 (m, 2H), 2.32 (s, 3H), 2.48 (s, 3H), 3.15-3.28 (m, 2H), 3.61 (s , 3H), 5.12-5.20 (m, 1H), 5.29 (s, 2H), 5.42-5.47 (m, 1H), 6.48 (d, 1H), 6.59-6.65 (m, 1H), 6.76 (d, 1H ), 6.90 (s, 1H), 7.19-7.26 (m, 2H), 7.55-7.64 (m, 1H), 8.23 (d, 1H), 8.39 (s, 1H).

Example 340 Racemic-N- (2-amino-2-methylpentyl) -8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxyfluorene amine

75 mg (0.15 mmol) of racemic- [1-({[8- (benzyloxy) -2,6-dimethylimidazo [1,2-a] pyridin-3-yl] from Example 329A) Carbonyl} amino) -2-methylpent-2-yl] carbamic acid third butyl ester was first put into 0.74 ml of diethyl ether, 0.74 ml (1.47 mmol) of 2N hydrochloric acid in diethyl ether was added and the mixture was stirred at RT Until overnight. 0.74 ml (1.47 mmol) of a 2N solution of hydrochloric acid in diethyl ether was added to the reaction mixture, and the mixture was stirred at RT overnight. The mixture was then concentrated, the residue was dissolved in dichloromethane and the solution was washed twice with saturated aqueous sodium bicarbonate solution. The combined organic phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 57 mg of the target compound (96% of theory).

LC-MS (Method 2): R _t = 0.67min

MS (ES +): m / z = 395 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 1.00 (s, 3H), 1.24-1.43 (m, 4H), 1.52-1.92 (m, 2H), 2.27 (s , 3H), 2.56 (s, 3H), 3.14-3.27 (m, 2H), 5.27 (s, 2H), 6.81 (s, 1H), 7.34-7.40 (m, 1H), 7.43 (t, 2H), 7.48-7.54 (m, 2H), 7.63 (t, 1H), 8.45 (s, 1H).

Example 341 Racemic-N- (3-amino-2,2-dimethylcyclopropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (racemate)

Add 0.5 ml of DMF and 0.39 ml (2.26 mmol) of N, N-diisopropylethylamine to 195 mg (1.13 mmol) of racemic-3,3-dimethylcyclopropane-1,2- Diamine dihydrochloride (described in: G.-Q. Feng et al. Tetrahedron: Asymmetry 2006, 17, 2775-2780). 150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine from Example 21A was stirred in advance at RT for 10 min. A solution of 3-carboxylic acid, 0.47 ml (2.71 mmol) of N, N-diisopropylethylamine and 206 mg (0.54 mmol) of HATU in 1.34 ml of DMF was added dropwise to the reaction mixture. The mixture was stirred at RT for 30 min, then water and TFA were added and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was concentrated. This gave 78 mg of the target compound (40% of theory).

LC-MS (Method 2): R _t = 0.61min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H NMR (500MHz, DMSO-d ₆ ) δ = 0.99 (s, 3 H), 1.14 (s, 3 H), 2.15-2.18 (m, 1 H), 2.28-2.32 (m, 4 H), 2.44 (s, 3 H), 5.28 (s, 2 H), 6.89 (s, 1 H), 7.23 (t, 2 H), 7.54-7.63 (m, 1 H), 7.79 (s, 1 H), 8.39 -8.43 (m, 1 H).

Example 342 Racemic-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- (octahydrocyclopenta [b] pyrrole-4-yl) imidazo [1,2-a] pyridine-3-carboxamide

115 mg (0.21 mmol) of racemic-4-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] hexahydrocyclopenta [b] pyrrole-1 (2H) -carboxylic acid third butyl ester was first put into 1 ml of diethyl ether, and 1 ml (2.13 mmol) of 2N hydrochloric acid was added And ether and the mixture was stirred at RT for 4 hours. The reaction mixture was concentrated, dichloromethane was added to the residue, and the mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was lyophilized. This gave 72 mg of the target compound (75% of theory).

LC-MS (Method 2): R _t = 0.57min

MS (ES +): m / z = 441 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.47-1.66 (m, 4H), 1.67-1.79 (m, 2H), 2.31 (s, 3H), 2.48 (s, 3H), 2.57-2.65 (m, 1H), 2.68-2.79 (m, 1H), 2.84-2.92 (m, 1H), 3.58 (t, 1H), 4.12-4.24 (m, 1H), 5.28 (s, 2H), 6.90 (s , 1H), 7.18-7.29 (m, 2H), 7.53-7.66 (m, 1H), 7.84 (d, 1H), 8.37 (s, 1H).

Example 343 Racemic-N- (2-amino-2-methylpentyl) -8-[(2-chlorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridin-3-carboxamide

80 mg (0.19 mmol) of racemic- (1-{[((8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino) from Example 330A ) -2-methylpent-2-yl) carbamate tert-butyl ester, 33 mg (0.21 mmol) of 2-chlorobenzyl chloride, 135 mg (0.41 mmol) of cesium carbonate and 3.1 mg (0.02 mmol) of potassium iodide Place in 3.6 ml of DMF and heat the mixture in a warm oil bath preheated to 60 ° C for 30 min. The reaction solution was concentrated and dried under high vacuum overnight. The residue was treated in 1 ml of diethyl ether, 0.94 ml (1.88 mmol) of 2N hydrochloric acid and diethyl ether were added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: methanol / water gradient with addition of 0.1% formic acid). The product fractions were combined and concentrated. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 49 mg of the target compound (61% of theory).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 429 (M + H) ⁺

Example 344 Racemic-N-[(4-benzylmorpholine-2-yl) methyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

20 mg (0.06 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 25 mg (0.07 mmol) of HATU and 0.05 ml (0.30 mmol) of N, N-diisopropylethylamine were first put into 0.4 ml of DMF, and the mixture was stirred for 20 min. Then 24.8 mg (0.12 mmol) of racemic-1- (4-benzylmorpholine-2-yl) methylamine was added at 0 ° C, and the mixture was stirred at 0 ° C for 60 min. Water / TFA was added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 31 mg of the target compound (94% of theory).

LC-MS (Method 2): R _t = 1.94min

MS (ES +): m / z = 521 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.78-1.88 (m, 1H), 2.05-2.15 (m, 1H), 2.30 (s, 3H), 2.37 (s, 3H), 2.60-2.67 (m, 1H), 2.74-2.80 (m, 1H), 3.25-3.31 (m, 2H), 3.42-3.46 (m, 1H), 3.47-3.57 (m, 2H), 3.58-3.66 (m, 1H) , 3.78-3.85 (m, 1H), 5.28 (s, 2H), 6.91 (s, 1H), 7.20-7.27 (m, 3H), 7.28-7.34 (m, 4H), 7.54-7.64 (m, 1H) , 7.87 (t, 1H), 8.37 (s, 1H).

Example 345 Racemic-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- (morpholin-2-ylmethyl) imidazo [1,2-a ] Pyridine-3-carboxamide

Under argon, 78 mg (0.15 mmol) of the racemic-N-[(4-benzylmorpholin-2-yl) methyl] -8-[(2,6-difluorobenzyl) from Example 344 (Yl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide is first placed in 1.6 ml of ethanol, and 16 mg (0.02 mmol) of 10% palladium on carbon is added The mixture was hydrogenated at RT and standard pressure for one hour. The reaction mixture was filtered through a Millipor filter, the filter cake was washed with ethanol and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 43 mg of the target compound (63% of theory).

LC-MS (Method 2): R _t = 0.61min

MS (ES +): m / z = 431 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.31 (s, 3H), 2.41-2.46 (m, 1H), 2.48 (s, 3H), 2.62-2.78 (m, 3H), 2.84-2.94 (m, 1H), 3.28-3.32 (m, 2H), 3.43-3.51 (m, 1H), 3.53-3.61 (m, 1H), 3.74-3.81 (m, 1H), 5.28 (s, 2H), 6.92 (s, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.88 (t, 1H), 8.42 (s, 1H).

Example 346 Racemic-N- (3-azabicyclo [3.2.0] hept-1-yl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide

95 mg (0.18 mmol) of racemic-1-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] -3-azabicyclo [3.2.0] Penta-3-carboxylic acid third butyl ester was first put into 0.9 ml of diethyl ether, and 0.88 ml (1.77 mmol) ) Of 2N hydrochloric acid in ether and the mixture was stirred at RT overnight. The reaction mixture was concentrated, dichloromethane and a drop of methanol were added to the residue, and the mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 70 mg of the target compound (90% of theory).

LC-MS (Method 2): R _t = 0.58min

MS (ES +): m / z = 427 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.38-1.48 (m, 1H), 2.03-2.15 (m, 2H), 2.21-2.29 (m, 1H), 2.31 (s, 3H), 2.48 (s, 3H), 2.65-2.74 (m, 2H), 2.83-2.95 (m, 2H), 3.11-3.18 (m, 1H), 5.28 (s, 2H), 6.90 (s, 1H), 7.20-7.28 (m, 2H), 7.54-7.64 (m, 1H), 8.08 (s, 1H), 8.42 (s, 1H).

Example 347 Racemic-8-[(2,6-difluorobenzyl) oxy] -N- (4-fluoropyrrolidin-3-yl) -2,6-dimethylimidazo [1,2-a ] Pyridine-3-carboxamide

98 mg (0.15 mmol) of racemic-3-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] -4-fluoropyrrolidine-1-carboxylic acid tert-butyl trifluoroacetate was first placed in 0.8 ml of diethyl ether, and 0.77 ml (1.54 mmol) of 2N was added. A solution of hydrochloric acid in ether and the mixture was stirred at RT overnight. An additional 0.77 ml (1.54 mmol) of a 2N solution of hydrochloric acid in diethyl ether was added to the reaction mixture, and the mixture was stirred at RT overnight. The reaction solution was concentrated and the residue was dissolved in dichloromethane and washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, concentrated and lyophilized. This gave 64 mg of the target compound (99% of theory).

LC-MS (Method 2): R _t = 0.63min

MS (ES +): m / z = 419 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.13-1.35 (m, 1H), 2.31 (s, 3H), 2.48 (s, 3H), 2.76 (t, 1H), 2.90-3.04 (m , 1H), 3.11 (dd, 1H), 3.23 (dd, 1H), 4.26-4.42 (m, 1H), 5.02-5.21 (m, 1H), 5.29 (s, 2H), 6.92 (s, 1H), 7.19-7.28 (m, 2H), 7.54-7.64 (m, 1H), 7.80 (d, 1H), 8.40 (s, 1H).

Example 348 Racemic-N- (2-amino-2-methylpentyl) -8-[(3-fluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridin-3-carboxamide

80 mg (0.19 mmol) of racemic- (1-{[((8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino) from Example 330A ) -2-methylpent-2-yl) carbamic acid third butyl ester, 39 mg (0.21 mmol) of 3-fluorobenzyl bromide, 135 mg (0.41 mmol) of cesium carbonate and 3.1 mg (0.02 mmol) of potassium iodide Place in 3.6 ml of DMF and heat the mixture in a warm oil bath preheated to 60 ° C for 30 min. The reaction solution was concentrated and dried under high vacuum overnight. The residue was treated in 0.9 ml of diethyl ether, 0.94 ml (1.88 mmol) of a 2N solution of hydrochloric acid in diethyl ether was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 51 mg of the target compound (64% of theory).

LC-MS (Method 2): R _t = 0.68min

MS (ES +): m / z = 413 (M + H) ⁺

Example 349 8-[(2,6-difluorobenzyl) oxy] -N- {2-[(2-hydroxyethyl) amino] -2-methylpropyl} -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide

100 mg (0.25 mmol) of N- (2-amino-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazole from Example 74 [1,2-a] pyridine-3-carboxamide was first put into 1 ml of DMF, and 0.023 ml (0.30 mmol) of iodoethanol and 69 mg (0.50 mmol) of potassium carbonate were added. The reaction mixture was stirred at RT overnight. 0.23 ml (3.0 mmol) of iodoethanol and 69 mg (0.50 mmol) of potassium carbonate were added, and the mixture was stirred under reflux overnight. The reaction mixture was diluted with water and acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and dried under high vacuum. This gave 5 mg of the target compound (4% of theory, 90% purity).

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 447 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6H), 1.54 (t, 1H), 2.31 (s, 3H), 3.24 (d, 2H), 3.28-3.31 (m, 1H ), 3.42 (q, 2H), 4.48 (t, 1H), 5.28 (s, 2H), 6.92 (s, 1H), 7.20-7.28 (m, 2H), 7.50 (t, 1H), 7.54-7.64 ( m, 1H), 8.52-8.56 (m, 1H).

Example 350 Racemic-N- [2-amino-3- (3,4-difluorophenoxy) -2-methylpropyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

51 mg (0.15 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 64.5 mg (0.17 mmol) of HATU and 0.13 ml (0.77 mmol) of N, N-diisopropylethylamine were first put into 1 ml of DMF, and the mixture was stirred for 20 min. At 0 ° C, then 40 mg (0.19 mmol) of racemic-3- (3,4-difluorophenoxy) -2-methylpropan-1,2-diamine from Example 391A was added, and the mixture was dissolved in Stir at 0 ° C for 45 min. Acetonitrile and TFA were added to the reaction solution, and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated and lyophilized. This gave 62 mg of the target compound (72% of theory).

LC-MS (Method 2): R _t = 0.80min

MS (ES +): m / z = 531 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.29 (s, 3H), 2.30 (s, 3H), 2.53 (br.s., 3H), 3.49-3.66 (m, 2H), 3.89- 3.96 (m, 1H), 3.98-4.05 (m, 1H), 5.29 (s, 2H), 6.78-6.85 (m, 1H), 6.94 (s, 1H), 7.04-7.13 (m, 1H), 7.20- 7.29 (m, 2H), 7.39 (q, 1H), 7.54-7.65 (m, 1H), 7.89 (t, 1H), 8.43 (s, 1H).

Example 351 Racemic-N- (2-amino-2-methylpentyl) -8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide

50 mg (0.14 mmol, purity 94%) of 8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 375A Pyridine-3-carboxylic acid, 57 mg (0.15 mmol) of HATU and 0.12 ml (0.68 mmol) of N, N-diisopropylethylamine were first put into 0.9 ml of DMF, and the mixture was stirred at RT for 20 min. At 0 ° C, then 28 mg (0.15 mmol) of racemic-2-methylpentan-1,2-diamine dihydrochloride from Example 326A was added, and the mixture was stirred at 0 ° C for 30 min. The reaction solution was diluted with water / TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 45 mg of the target compound (71% of theory).

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 443 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.87 (t, 3H), 1.00 (s, 3H), 1.22-1.44 (m, 4H), 1.72-2.11 (m, 2H), 2.31 (s , 3H), 2.52 (s, 3H), 3.15-3.27 (m, 2H), 3.85 (s, 3H), 5.18 (s, 2H), 6.87-6.95 (m, 2H), 6.99 (d, 1H), 7.44-7.53 (m, 1H), 7.62 (t, 1H), 8.44 (s, 1H).

Example 352 N- (2-amino-2-methylpropyl) -8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2- a] pyridine-3-carboxamide

50 mg (0.14 mmol, purity 94%) of 8-[(2-fluoro-6-methoxybenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 375A Pyridine-3-carboxylic acid, 57 mg (0.15 mmol) of HATU and 0.07 ml (0.41 mmol) of N, N-diisopropylethylamine were first put into 0.9 ml of DMF, and the mixture was stirred at RT for 20 min. At 0 ° C, 0.02 ml (0.15 mmol) of 1,2-diamino-2-methylpropane was then added, and the mixture was stirred at 0 ° C for 30 min. The reaction solution was diluted with water / TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 48 mg of the target compound (83% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 415 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 1.05 (s, 6H), 1.47-1.78 (m, 2H), 2.31 (s, 3H), 2.52 (s, 3H), 3.20 (d, 2H ), 3.85 (s, 3H), 5.18 (s, 2H), 6.86-6.95 (m, 2H), 6.99 (d, 1H), 7.49 (q, 1H), 7.65 (t, 1H), 8.44 (s, 1H).

Example 353 N- (2-amino-2-methylpentyl) -8-[(2-bromobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3- Carboxamide

80 mg (0.19 mmol) of racemic- (1-{[((8-hydroxy-2,6-dimethylimidazo [1,2-a] pyridin-3-yl) carbonyl] amino}}-2 -Methylpent-2-yl) carbamic acid third butyl ester 330A, 53 mg (0.21 mmol) of 2-bromobenzyl bromide, 135 mg (0.41 mmol) of cesium carbonate, and 3.1 mg (0.02 mmol) of potassium iodide were placed first In 3.6 ml of DMF, and the mixture was heated in a warm oil bath preheated to 60 ° C for 30 min. The reaction solution was concentrated and dried under high vacuum overnight. The residue was treated in diethyl ether, 0.94 ml (1.88 mmol) of 2N hydrochloric acid in diethyl ether was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, the filtrate was concentrated and the residue was lyophilized. This gave 60 mg of the target compound (67% of theory).

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 473 (M + H) ⁺

Example 354 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxyfluorene amine

Under argon, 117 mg (0.18 mmol) of the enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy] imidazo [1,2-a] pyridine from Example 376A -3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl trifluoroacetate was first put into 1.9 ml of ethanol, and 19.2 mg (0.02 mmol) of 10% carbon was added Palladium was applied and the mixture was hydrogenated at RT and standard pressure for 1 hour. The reaction mixture was adsorbed on diatomaceous earth and purified by silica gel chromatography (mobile phase: dichloromethane / 2N ammonia methanol solution = 40/1 to 30/1). This gave 30 mg of the target compound (41% of theory).

LC-MS (Method 2): R _t = 0.67min

MS (ES +): m / z = 403 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 0.86 (t, 4 H), 0.95 (s, 3 H), 1.18-1.43 (m, 4 H), 1.44-1.56 (m, 1 H), 3.12 -3.23 (m, 2 H), 5.34 (s, 2 H), 6.99-7.11 (m, 2 H), 7.24 (t, 2 H), 7.53-7.65 (m, 1 H), 8.17-8.26 (m , 1 H), 8.31 (s, 1 H), 9.08 (d, 1 H).

Example 355 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6-ethynyl-2-methylimidazo [1, 2-a] pyridine-3-carboxamidate

At 0 ° C, 161 mg (0.28 mmol) of the enantiomer- {1-[({8-[(2,6-difluorobenzyl) oxy]]-6-ethynyl-2-methylimidazole from Example 359A [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester and 0.2 ml of anisole were first placed in 2.5 ml of dichloro In methane, 2.5 ml of a 70% strength hydrogen fluoride pyridine solution was added. The mixture was then stirred at RT for 6 h and stored at -20 ° C overnight. The reaction mixture was diluted with 20 ml of dichloromethane and added dropwise to 100 ml of a saturated sodium bicarbonate aqueous solution at 0 ° C, and the mixture was stirred at 0 ° C for 30 min. The two phases were separated and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution and once with water, then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 107 mg (78% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.76min

MS (ES +): m / z = 441 (M-HCO ₂ H + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.86-0.93 (d, 3H), 1.14 (s, 3H), 1.30-1.55 (m, 4H), 2.56 (s, 3H), 3.30-3.45 (m, 2H), 4.34 (s, 1H), 5.33 (s, 2H), 7.08 (d, 1H), 7.20-7.29 (m, 2H), 7.55-7.65 (m, 1H), 8.14 ( br.s, 1H), 8.32 (s, 1H), 8.79 (s, 1H).

Example 356 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6-ethynyl-2-methylimidazo [1, 2-a] pyridine-3-carboxamide

88 mg (0.18 mmol) of the enantio-N- (2-amino-2-methyl) from Example 355 Amyl) -8-[(2,6-difluorobenzyl) oxy] -6-ethynyl-2-methylimidazo [1,2-a] pyridine-3-carboxamidate Wash twice in dichloromethane with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 79 mg of the title compound (99% of theory).

LC-MS (Method 2): R _t = 0.78min

MS (ES +): m / z = 441 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.82-0.90 (m, 3H), 1.00 (s, 3H), 1.25-1.41 (m, 4H), 1.68-2.15 (br.s , 2H), 3.17-3.32 (m, 2H), 4.32 (s, 1H), 5.33 (s, 2H), 7.07 (s, 1H), 7.20-7.28 (m, 2H), 7.55-7.66 (m, 1H ), 7.76 (br.s, 1H), 8.80 (s, 1H), [additional signal under solvent peak].

Example 357 Enantiomer-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide hydrochloride (mirromeric isomer A)

302 mg (0.71 mmol) of enantio-N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6- from Example 200 Dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A) was first placed in 5.7 ml of diethyl ether, 0.43 ml (0.85 mmol) of a 2N solution of hydrochloric acid in ether and The mixture was stirred at room temperature for 30 min. The solvent was then evaporated. This gave 326 mg of the target compound (99% of theory).

LC-MS (Method 2): R _t = 0.64min

MS (ESI +): m / z = 417 (M-HCl + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 0.95 (t, 3H), 1.24 (s, 3H), 1.55-1.73 (m, 2H), 2.34 (s, 3H), 2.57 (s, 3H ), 3.41-3.56 (m, 2H), 5.32 (s, 2H), 7.06 (br.s, 1H), 7.19-7.30 (m, 2H), 7.54-7.66 (m, 1H), 7.87 (br.s 3H), 8.11 (br.s, 1H), 8.50 (s, 1H).

Example 358 N- (2-amino-3,3-dimethylcyclobutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamidate (isomer mixture)

200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 21A) , 218 mg (0.57 mmol) of HATU and 308 mg (2.39 mmol) of N, N-diisopropylethylamine were first put into 3.5 ml of DMF, and the mixture was stirred at RT for 10 min. The reaction mixture was then added dropwise to 296 mg (1.50 mmol) of 3,3-dimethylcyclobutane-1,2-diamine dihydrochloride (mixture of isomers; described by K. Scholz et al. Liebigs Annalen der Chemie, 1981, (2), 248-55; D. Hossain et al. Synthetic Communications 2012 42, 1200-1210; M. Klapper et al. Angewandte Chemie 2003, 115, 4835-4690) and 467 mg (3.61 mmol) of N , N-Diisopropylethylamine was dissolved in a mixture of 0.7 ml of DMF, and the mixture was stirred at RT for 30 min. The reaction mixture was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 131 mg (44% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 429 (M + H) ⁺

Example 359 Enantiomer-N- (2-amino-2-methylpentyl) -8-[(3-cyclopropyl-2,6-difluorobenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide

159 mg (0.21 mmol) of the enantiomer- {1-[({8-[(3-cyclopropyl-2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazole from Example 383A Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate and 45 mg (0.04 mmol) on 10% carbon A mixture of palladium hydroxide in 5.4 ml of ethanol was hydrogenated at RT and standard pressure for 1 h. The mixture was then filtered through a Millipore filter. The filtrate was concentrated and the residue was purified by thin layer chromatography (dichloromethane / methanol = 10/1). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 75 mg of the title compound (73% of theory).

LC-MS (Method 2): R _t = 0.81min

MS (ES +): m / z = 471 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.71-078 (m, 2H), 0.83-0.91 (m, 3H), 0.94-1.04 (m, 5H), 1.26-1.41 (m , 4H), 2.00-2.09 (m, 1H), 2.31 (s, 3H), 3.16-3.28 (m, 2H), 5.27 (s, 2H), 6.92 (s, 1H), 7.07-7.22 (m, 2H ), 7.61-7.69 (m, 1H), 8.47 (s, 1H), [additional signal under solvent peak].

The examples shown in Table 15 are similar to Example 359 by applying the appropriate Cbz-protected amine Prepared by hydrogenation of palladium / carbon (10%; 0.1-0.3 equivalents) in ethanol at RT and standard pressure under the reaction conditions described. Here, the reaction time is between 1h and 3h.

Example 364 Enantio-N- (2-amino-2-methylpentyl) -8-[(2,6-difluoro-3-methoxybenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide

205 mg (0.28 mmol) of the enantiomer of Example 386A- {1-[({8-[(2,6-difluoro-3-methoxybenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -2-methylpent-2-yl} carbamic acid benzyl ester trifluoroacetate and 59 mg (0.06 mmol) on 10% carbon A mixture of palladium hydroxide in 7.1 ml of ethanol was hydrogenated at RT and standard pressure for 2 h. Then mix The material was filtered through a Millipore filter. The filtrate was concentrated on a rotary evaporator and the residue was purified by thin layer chromatography (dichloromethane / methanol = 7.5 / 1). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 80 mg of the title compound (63% of theory).

LC-MS (Method 2): R _t = 0.69min

MS (ES +): m / z = 461 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 0.87 (t, 3H), 0.99 (s, 3H), 1.24-1.40 (m, 4H), 1.50-1.90 (br.s, 2H ), 2.30 (s, 3H), 3.14-3.26 (m, 2H), 3.87 (s, 3H), 5.28 (s, 2H), 6.91 (s, 1H), 7.13-7.21 (m, 1H), 7.28- 7.37 (m, 1H), 7.58-7.67 (m, 1H), 8.47 (s, 1H) [additional signal under solvent peak].

Example 365 N- (3-Amine Fundadamant-1-yl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine- 3-carboxamidate

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid (Example 21A) 206 mg (0.54 mmol) of HATU and 117 mg (0.90 mmol) of N, N-diisopropylethylamine were first placed in 1.3 ml of DMF, and the mixture was stirred at RT for 10 min. At 60 ° C, the mixture was then added dropwise to 324 mg (1.35 mmol) of adamantane-1,3-diamine dihydrochloride (G. Senchyk et al. Inorganica Chimica Acta, 2009, 362 (12), 4439-4448) and 700 mg (5.42 mmol) of N, N-diisopropylethylamine in a mixture of 0.6 ml of DMF and 3.2 ml of DMSO, and the mixture was stirred at 60 ° C for 1 h. The reaction mixture was cooled and filtered. The filtrate was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 60 mg (25% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.66min

MS (ES +): m / z = 481 (M + H) ⁺

Example 366 Racemic-8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl-N- (thiamorpholin-3-ylmethyl) imidazo [1,2- a] pyridine-3-carboxamide

13 mg (0.1 mmol) of 1- (timorpholin-3-yl) methylamine (see A. Eremev et al., Zhurnal Organicheskoi Khimii, 21 (10), 2239-41; 1985) was first placed in a 96-well depth Multi-titration wells. 33 mg (0.1 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was continuously added 0.3 ml of DMF solution and 45 mg (0.12 mmol) of 0.3 ml of DMF of HATU. After adding 20 mg (0.2 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. The mixture was then filtered, and the target compound was isolated from the filtrate by preparative LC-MS (Method 12). The product-containing fraction was concentrated in a centrifugal dryer under reduced pressure. The residue of product dissolution was dissolved in 0.6 ml of DMSO each time. These solutions were combined and then the solvent was removed in a centrifugal dryer. This gave 17.8 mg (39% of theory).

LC-MS (Method 8): R _t = 0.65min

MS (ES +): m / z = 447 (M + H) ⁺

The exemplary compounds shown in Table 16 are similar to Example 366 by 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 21A Pyridine-3-carboxylic acid is prepared by reacting with an appropriate commercially available or the aforementioned amine under the conditions described:

Example 377 Racemic-N- {2-amino-2- [3- (trifluoromethoxy) phenyl] ethyl} -8-[(2,6-difluorobenzyl) oxy] -2, 6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

In a round bottom flask, 100 mg (0.31 mmol) of {2-amino-2- [3- (trifluoromethoxy) phenyl] ethyl} carbamic acid third butyl ester was dissolved in 2 ml of dichloromethane. , Add 2ml (8mmol) of hydrogen chloride bis Solution (4M) and the mixture was stirred at RT for 4 hours. The mixture was then evaporated to dryness and the resulting 30 mg of solid was transferred to a 96-well deep well multi-titer plate. 33 mg (0.1 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was continuously added 0.3 ml of DMF solution and 49 mg (0.13 mmol) of HATU in 0.3 ml of DMF solution, then 20 mg (0.2 mmol) of 4-methylmorpholine was added and the mixture was shaken at RT overnight. The reaction mixture was then filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 12). The product-containing fraction was concentrated under reduced pressure using a centrifugal dryer. The residue of product dissolution was dissolved in 0.6 ml of DMSO each time. These solutions were combined and then the solvent was removed in a centrifugal dryer. This gave 10.3 mg (19% of theory).

LC-MS (Method 8): R _t = 0.75min

MS (ES +): m / z = 535 (M + H) ⁺

The exemplary compounds shown in Table 17 are similar to Example 377 by 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 21A Pyridine-3-carboxylic acid is prepared by reacting with an appropriate commercially available or the aforementioned amine under the conditions described:

Example 379 Racemic-N- [2-amino-1- (2-naphthyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide

29 mg (0.1 mmol) of [2-amino-2- (2-naphthyl) ethyl] carbamic acid third butyl ester was first placed in a 96-well deep well multi-titer plate. 33 mg (0.1 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was continuously added 0.3 ml of DMF solution and 45 mg (0.12 mmol) of 0.3 ml of DMF of HATU. Join 20 After mg (0.2 mmol) of 4-methylmorpholine, the mixture was shaken at RT overnight. The solvent was then completely evaporated, 0.6 ml of TFA was added to the residue and the mixture was shaken at RT overnight. The mixture was then evaporated, the residue was redissolved in DMF and filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 12). The product-containing fraction was concentrated under reduced pressure using a centrifugal dryer. The residue of product dissolution was dissolved in 0.6 ml of DMSO each time. These solutions were combined and then the solvent was removed in a centrifugal dryer. This gave 25.8 mg (49% of theory; purity 94%).

LC-MS (Method 8): R _t = 0.76min

MS (ES +): m / z = 501 (M + H) ⁺

The exemplary compounds shown in Table 18 are similar to Example 379 by 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 21A Pyridine-3-carboxylic acid is prepared by reacting with an appropriate commercially available or the aforementioned amine under the conditions described:

Example 385 Racemic-N- [2-amino-1- (3-vinylphenyl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl Imidazo [1,2-a] pyridine-3-carboxamide

16 mg (0.1 mmol) of 1- (3-vinylphenyl) ethane-1,2-diamine was first placed in a 96-well deep well multi-titer plate, and 0.2 ml of dichloromethane and 22 mg (0.1 mmol) were continuously added. ) Of 0.2 ml of di-tert-butyl carbonate in dichloromethane, and shake the mixture at RT for 2 hours. In a flask, 33 mg (0.1 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3 from Example 21A -The carboxylic acid and 49 mg (0.13 mmol) of HATU were dissolved in 0.4 ml of DMF, 20 mg (0.2 mmol) of 4-methylmorpholine was added and the mixture was stirred at RT for 30 min. The mixture was then pipetted onto a multi-titer plate and the plate was shaken at RT for 48 hours. The solvent was completely evaporated, and 0.6 ml of TFA was added to the residue and the mixture was shaken at RT overnight. The mixture was then concentrated, the residue was dissolved in DMF and filtered and the target compound was isolated from the filtrate by preparative LC-MS (Method 12). The product-containing fraction was concentrated under reduced pressure using a centrifugal dryer. The residue of product dissolution was dissolved in 0.6 ml of DMSO each time. These solutions were combined and then the solvent was removed in a centrifugal dryer. This gave 2.9 mg (6% of theory).

LC-MS (Method 8): R _t = 0.72min

MS (ES +): m / z = 477 (M + H) ⁺

The exemplary compounds shown in Table 19 are similar to Example 385 by 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] from Example 21A Pyridine-3-carboxylic acid is prepared by reaction with an appropriate commercially available or the above amine under the conditions described: Table 19:

Example 396 Racemic-N- [1- (3-Ethylaminophenyl) -2-aminoethyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide

100 mg (0.14 mmol) was obtained from racemic Example 414A- {2- (3-acetamidophenyl) -2-[({8-[(2,6-difluorobenzyl) oxy]- 2,6-dimethylimidazo [1,2-a] pyridin-3-yl} carbonyl) amino] ethyl} carbamic acid third butyl trifluoroacetate was first put into 0.6 ml of ether and added 2.1 ml (4.2 mmol) of a 2N solution of hydrogen chloride in diethyl ether and the mixture was stirred at RT overnight. The reaction mixture was concentrated, dichloromethane was added to the residue, and the mixture was washed twice with a saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 52 mg of the target compound (72% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 508 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 1.62 (br.s, 2H), 2.02 (s, 3H), 2.29 (s, 3H), 2.60 (s, 3H), 2.89 ( d, 2H), 4.86-4.94 (m, 1H), 5.29 (s, 2H), 6.90 (s, 1H), 7.07 (d, 1H), 7.19-7.28 (m, 3H), 7.43 (d, 1H) , 7.54-7.63 (m, 2H), 8.11 (br.s, 1H), 8.38 (s, 1H), 9.89 (s, 1H).

The example compounds shown in Table 20 are similar to Example 396 prepared by reacting the above Boc-protected diamine with a hydrogen chloride solution under the reaction conditions described.

Table 20:

Example 399 Racemic-3- {1-amino-2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridine -3-yl} carbonyl) amino] ethyl} methyl benzate

100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 126 mg (0.33 mmol) of HATU and 117 mg (0.90 mmol) of N, N-diisopropylethylamine were first placed in 1 ml of DMF, and the mixture was stirred at RT for 10 min. Then 67 mg (0.35 mmol) of racemic methyl 3- (1,2-diaminoethyl) benzoate was added and the mixture was stirred at RT for 2 h. Acetonitrile, TFA, and water were added to the reaction mixture, and the product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, and the filtrate was concentrated. This gave 21 mg (13% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.70min

MS (ES +): m / z = 509 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 2.11 (br.s, 2H), 2.28 (s, 3H), 2.35 (s, 3H), 3.38-3.46 (m, 1H), 3.48-3.56 (m, 1H), 3.72 (s, 3H), 4.18 (t, 1H), 5.29 (s, 2H), 6.88 (s, 1H), 7.19-7.26 (m, 2H), 7.48 (t, 1H), 7.55-7.64 (m, 1H), 7.70 (d, 1H), 7.78 (t, 1H), 7.83 (d, 1H), 8.03 (s, 1H), 8.28 (s, 1H).

Example 400 Racemic-N- (2-amino-2-cyanoethyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide

200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was first Into 1.8 ml of DMF, 252 mg (0.66 mmol) of HATU and 311 mg (2.41 mmol) of N, N-diisopropylethylamine were added and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 ° C. 109 mg (0.69 mmol) of racemic-2,3-diaminopropionitrile dihydrochloride (commercially available; see also AHCook et al. Journal of the Chemical Society 1949, 3001) and 194 mg (0.69 mmol) were slowly added dropwise. 1.51 mmol) of a solution of N, N-diisopropylethylamine in 0.67 ml of DMF, and the mixture was stirred at 0 ° C. for 1 h. The reaction solution was diluted with TFA / water and acetonitrile and the product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient addition of 0.1% TFA). The concentrated residue was treated in dichloromethane and a little methanol and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 197 mg of the title compound (79% of theory).

LC-MS (Method 2): R _t = 0.65min

MS (ES +): m / z = 400 (M + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.30 (s, 3H), 2.50 (s, 3H), 3.40-3.60 (m, 2H), 3.95-4.08 (m, 1H), 5.29 (s, 2H), 6.92 (s, 1H), 7.18-7.28 (m, 2H), 7.54-7.63 (m, 1H), 8.10 (t, 1H), 8.45 (s, 1H).

Example 401 Enantio-N- (2-amino-2-cyanoethyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer A)

170 mg of racemic-N- (2-amino-2-cyanoethyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl from Example 400 Imidazolo [1,2-a] pyridine-3-carboxamide is separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralpak AD-H, 5μm, SFC, 250 × 20mm, Mobile phase: 70% carbon dioxide, 30% ethanol, flow rate: 80ml / min, temperature: 40 ° C, detection: 210nm].

Mirror isomer A: 70mg (> 99% ee)

R _t = 7.67min [SFC, Daicel Chiralpak AD-H, 250 × 4.6mm, 5μm, mobile phase: 70% carbon dioxide, 30% ethanol, flow rate: 3ml / min, temperature: 30 ° C, detection: 220nm].

Example 402 Enantio-N- (2-amino-2-cyanoethyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer B)

170 mg of racemic-N- (2-amino-2-cyanoethyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethyl from Example 400 Imidazolo [1,2-a] pyridine-3-carboxamide is separated into mirror isomers by preparative separation on the palm phase [column: Daicel Chiralpak AD-H, 5μm, SFC, 250 × 20mm, Mobile phase: 70% carbon dioxide, 30% ethanol, flow rate: 80ml / min, temperature: 40 ° C, detection: 210nm].

Mirror isomer B: 60mg (> 99% ee)

R _t = 12.45min [SFC, Daicel Chiralpak AD-H, 250 × 4.6mm, 5μm, mobile phase: 70% carbon dioxide, 30% ethanol, flow rate: 3ml / min, temperature: 30 ° C, detection: 220nm].

Example 403 Enantiomer-N- (2-amino-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -6- (fluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxamide

171 mg (0.21 mmol, 87% purity) of the enantiomer-{1-[({8-[(2,6-difluorobenzyl) oxy]]-6- (fluoromethyl) -2- from Example 401A Methylimidazo [1,2-a] pyridin-3-yl} carbonyl (Amino) amino] -2-methylpent-2-yl} carbamic acid benzyl trifluoroacetate and 11.4 mg of 10% palladium on carbon (0.01 mmol) in 17 ml of ethanol at room temperature and standard pressure Hydrogenated for 2h. During the reaction, an additional 20 mg of 10% palladium on carbon (0.02 mmol) was added to the reaction mixture. The mixture was then filtered through a filter, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude wasp was repurified by thick layer chromatography (mobile phase: dichloromethane / methanol 10/1). The obtained repurified product was repurified on the palm phase [column: Daicel Chiralpak AY-H 5 μm, 250 × 20 mm; mobile phase: 70% isohexane, 30% isopropanol + 0.2% diethylamine; 20ml / min; temperature 23 ° C; detection 220nm]. This gave 13 mg of the title compound (13% of theory).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 449 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 0.82-0.92 (m, 3H), 1.01 (s, 3H), 1.25-1.47 (m, 4H), 1.95-2.30 (br.s , 2H), 2.56 (s, 3H), 3.14-3.27 (m, 2H), 5.33 (s, 2H), 5.47 (d _HF , 2H), 7.11 (s, 1H), 7.21-7.28 (m, 2H) , 7.55-7.64 (m, 1H), 7.69-7.78 (m, 1H), 8.77-8.81 (m, 1H).

The exemplary compound shown in Table 21 is similar to Example 403, and was prepared by hydrogenating the Cbz-protected amine from Example 402A and Example 403A described above under the conditions described:

Example 406 Racemic-N-[(4E / Z) -2-aminohex-4-en-1-yl] -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide

200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was first Into 1.8 ml of DMF, 252 mg (0.66 mmol) of HATU and 467 mg (3.61 mmol) of N, N-diisopropylethylamine were added and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 ° C. 130 mg (0.69 mmol) of racemic- (4E / Z) -hex-4-ene-1,2-diamine dihydrochloride and 194 mg (1.51 mmol) of N, N-diisopropyl were added dropwise. A solution of 0.67 ml of ethylamine in DMF, and the mixture was stirred at 0 ° C for 1 h. The reaction solution was diluted with TFA / water and acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient addition of 0.1% TFA). The concentrated residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 114 mg of the title compound (42% of theory, 94% purity).

LC-MS (Method 2): R _t = 0.65min

MS (ES +): m / z = 429 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 1.56-1.67 (m, 3H), 1.94-2.08 (m, 1H), 2.09-2.23 (m, 1H), 2.31 (s, 3H ), 2.50 (s, 3H), 2.83-2.94 (m, 1H), 3.07-3.18 (m, 1H), 3.29-3.41 (m, 1H), 5.29 (s, 2H), 5.42-5.58 (m, 2H ), 6.91 (s, 1H), 7.19-7.27 (m, 2H), 7.54-7.63 (m, 1H), 7.68-7.78 (m, 1H), 8.47 (m, 1H).

Example 407 Racemic-6- {1-amino-2-[({8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] Pyridin-3-yl} carbonyl) amino] ethyl} pyridine-2-carboxylic acid ethyl ester

35 mg (0.11 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A was first Into 0.32 ml of DMF, 45 mg (0.12 mmol) of HATU and 55 mg (0.43 mmol) of N, N-diisopropylethylamine were added and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 ° C. Slowly, 106 mg (0.13 mmol) of racemic-6- (1,2-diaminoethyl) pyridine-2-carboxylic acid ethyl ester dihydrochloride (from 6- {1-amino- 2-[(Third-butoxycarbonyl) amino] ethyl} pyridine-2-carboxylic acid ethyl ester prepared by treating with 2N hydrochloric acid in diethyl ether and concentrating the reaction mixture) and 50 mg (0.38 mmol) of N N-diisopropylethylamine in 0.12 ml of a DMF solution, and the mixture was stirred at 0 ° C for 1 h. The reaction solution was diluted with TFA / water and acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient addition of 0.1% TFA). The product fractions were concentrated and the residue was treated with dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was repurified by thick layer chromatography (mobile phase: dichloromethane / methanol = 10/1). This gave 8.5 mg of the title compound (9% of theory, 65% purity).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 524 (M + H) ⁺

Example 408 Enantiomer-N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide (Mirror image isomer A)

1.02 g (1.56 mmol) of the enantiomer-{1-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2 -a] pyridin-3-yl} carbonyl) amino] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer A) and 332 mg of 10 A mixture of palladium on 40% activated carbon in 40 ml of ethanol was hydrogenated at room temperature and standard pressure for 2 h. The mixture was then filtered through celite, the filter cake was washed with ethanol and the filtrate was concentrated. The crude product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 601 mg of the title compound (79% of theory).

LC-MS (Method 2): R _t = 0.73min

MS (ES +): m / z = 485 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 1.02 (s, 3H), 1.48-1.56 (m, 2H), 1.60 (br.s, 2H), 2.27-2.46 (m, 5H ), 2.50 (s, 3H; overlapping with solvent peaks), 3.18-3.29 (m, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.19-7.27 (m, 2H), 7.54-7.63 ( m, 1H), 7.73-7.80 (m, 1H), 8.41 (s, 1H).

Mirror isomer A: about 97% ee

R _t = 5.77min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 35 ° C; detection : 220nm].

Example 409 Enantiomer-N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

965 mg (1.56 mmol) of the enantiomer-{1-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2- a] Pyridin-3-yl} carbonyl) amino] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer B) and 332 mg of 10% A mixture of activated carbon on palladium in 40 ml of ethanol was hydrogenated at room temperature and standard pressure for 2 h. The mixture was then filtered through celite, the filter cake was washed with ethanol and the filtrate was concentrated. The crude product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 586 mg of the title compound (77% of theory).

LC-MS (Method 2): R _t = 0.72min

MS (ES +): m / z = 485 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 1.02 (s, 3H), 1.48-1.56 (m, 2H), 1.59 (br.s, 2H), 2.27-2.46 (m, 5H ), 2.50 (s, 3H; overlapping with solvent peaks), 3.18-3.29 (m, 2H), 5.29 (s, 2H), 6.91 (s, 1H), 7.19-7.27 (m, 2H), 7.54-7.63 ( m, 1H), 7.73-7.80 (m, 1H), 8.41 (s, 1H).

Mirror isomer B: about 78% ee

R _t = 5.02min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 35 ° C; detection : 220nm].

The title compound was purified as follows: 280 mg of the mirror image isomer B (about 78% ee) from the above mirror image isomer was separated into the mirror image isomer by preparative separation [column: Daicel Chiralpak IF , 5μm, 250 × 20mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 50ml / min, temperature: 23 ° C; detection: 220nm]. The product fractions were collected on dry ice and concentrated, acetonitrile / water was added and the product was lyophilized.

Mirror isomer B: 158mg (> 99% ee; purity about 97%)

R _t = 5.05min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 35 ° C; detection : 220nm].

Example 410 Enantiomer-N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl ) Oxy] imidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer A)

550 mg (0.75 mmol, 87% purity) of enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazole) from Example 412A Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer A ) And 160 mg of 10% activated carbon in a mixture of palladium in 19.4 ml of ethanol was hydrogenated at room temperature and standard pressure for 2 h. The mixture was then filtered through celite, the filter cake was washed with ethanol and the filtrate was concentrated. The crude product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). Product The fraction was treated in dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 262 mg of the title compound (69% of theory).

LC-MS (Method 2): R _t = 0.74min

MS (ES +): m / z = 503 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 1.03 (s, 3H), 1.49-1.57 (m, 2H), 1.75 (br.s, 2H), 2.27-2.46 (m, 5H ), 2.50 (s, 3H; overlapping with solvent peaks), 3.18-3.29 (m, 2H), 5.34 (s, 2H), 6.91 (s, 1H), 7.25-7.32 (m, 1H), 7.61-7.70 ( m, 1H), 7.75-7.82 (m, 1H), 8.42 (s, 1H).

Mirror isomer A: about 98% ee

R _t = 5.70min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 35 ° C; detection : 220nm].

Example 411 Enantiomer-N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl ) Oxy] imidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

535 mg (0.75 mmol) of the enantiomer- {1-[({2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1, 2-a] pyridin-3-yl} carbonyl) amino] -5,5,5-trifluoro-2-methylpent-2-yl} carbamic acid benzyl ester (mirror isomer B) and 173 mg of A mixture of 10% activated carbon on palladium in 21 ml of ethanol was hydrogenated at room temperature and standard pressure for 2 h. Then pass the mixture through Filter through celite, wash the filter cake with ethanol and concentrate the filtrate. The crude product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 262 mg of the title compound (68% of theory).

LC-MS (Method 2): R _t = 0.71min

MS (ES +): m / z = 503 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 1.03 (s, 3H), 1.48-1.56 (m, 2H), 1.60 (br.s, 2H), 2.27-2.46 (m, 5H ), 2.50 (s, 3H; overlapping with solvent peaks), 3.18-3.29 (m, 2H), 5.34 (s, 2H), 6.91 (s, 1H), 7.25-7.32 (m, 1H), 7.61-7.70 ( m, 1H), 7.74-7.81 (m, 1H), 8.42 (s, 1H).

Mirror isomer B: about 78% ee

R _t = 4.90min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 35 ° C; detection : 220nm].

The title compound was further purified as follows: 140 mg of mirror image isomer B (about 78% ee) from the above mirror image isomer separation was separated into the mirror image isomer by preparative separation [column: Daicel Chiralpak IF, 5μm, 250 × 20mm, mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine, flow rate: 20ml / min, temperature: 23 ° C; detection: 220nm]. The product fractions were collected on dry ice and concentrated, acetonitrile / water was added and the product was lyophilized.

Mirror isomer B: 97mg (> 99% ee; purity about 98%)

R _t = 4.93min [Daicel Chiralpak AZ-H, 5μm, 250 × 4.6mm; mobile phase: 50% isohexane, 50% ethanol + 0.2% diethylamine; flow rate 1.0ml / min; temperature: 35 ° C; detection : 220nm].

Example 412 Racemic-N- [2-amino-4- (methylsulfanyl) butyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide

150 mg (0.45 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 189 mg (0.50 mmol) of HATU and 175 mg (1.35 mmol) of N, N-diisopropylethylamine were first placed in 2 ml of DMF, and the mixture was stirred at RT for 10 min. The reaction mixture was then added dropwise at 0 ° C to 112 mg (0.54 mmol) of racemic-4- (methylsulfanyl) butane-1,2-diamine dihydrochloride and 175 mg (1.35 mmol) N, N-diisopropylethylamine was dissolved in 0.26 ml of a mixture of DMF. The mixture was stirred at 0 ° C for 1 h and then at RT for 30 min. Water / TFA / acetonitrile was added to the reaction solution, and the product was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fraction was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 106 mg (51% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.60min

MS (ES +): m / z = 449 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 1.42-1.52 (m, 1H), 1.62-1.93 (m, 3H), 2.07 (s, 3H), 2.30 (s, 3H), 2.49-2.68 (m, 5H; part overlaps with solvent peak), 2.86-2.94 (m, 1H), 3.17-3.23 (m, 1H), 3.25-3.39 (m, 1H; overlap with solvent peak); 5.29 (s, 2H ), 6.91 (s, 1H), 7.19-7.26 (m, 2H), 7.55-7.64 (m, 1H), 7.73-7.79 (m, 1H), 8.47 (s, 1H).

Example 413 Racemic-N- [2-amino-4- (methylsulfonyl) butyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazole Benzo [1,2-a] pyridine-3-carboxamide

88 mg (0.20 mmol) of racemic-N- [2-amino-4- (methylsulfanyl) butyl] -8-[(2,6-difluorobenzyl) oxy from Example 412 ] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide is first put into 2 ml of dichloromethane, and the mixture is cooled to 0 ° C and added in small amounts at each time Add 3-chloroperoxybenzoic acid. The mixture was stirred at 0 ° C for 30 min. The mixture was then diluted with dichloromethane, and the filtrate was washed once with 1N aqueous sodium hydroxide solution and water. The mixture was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. This gave 53 mg (55% of theory; 98% purity) of the title compound.

LC-MS (Method 2): R _t = 0.56min

MS (ES +): m / z = 481 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ = 1.57-1.64 (m, 1H), 1.72 (br.s, 2H), 1.84-1.93 (m, 1H), 2.30 (s, 3H), 2.50 (s, 3H; under solvent peak), 2.87-3.00 (m, 4H), 3.14 -3.32 (m, 4H; overlap with solvent peak), 5.29 (s, 2H), 6.91 (s, 1H), 7.19- 7.26 (m, 2H), 7.55-7.64 (m, 1H), 7.81 (t, 1H), 8.47 (s, 1H).

Example 414 Racemic-8-[(2,6-difluorobenzyl) oxy] -N-[(1,1-dioxotimorpholin-3-yl) methyl] -2,6-dimethyl Imidazo [1,2-a] pyridine-3-carboxamide

59 mg (0.09 mmol) of racemic-3-{[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazo [1,2 -a] pyridin-3-yl} carbonyl) amino] methyl} thiamorpholine-4-carboxylic acid tert-butyl 1,1-dioxide trifluoroacetate dissolved in 0.5 ml of ether and added 1.28 ml (2.56 mmol) of 2N hydrochloric acid in ether. The reaction mixture was stirred at room temperature overnight. The mixture was then concentrated and the crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with addition of 0.1% TFA). The product fractions were concentrated and the residue was treated with dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 30 mg of the target compound (74% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ESI +): m / z = 479 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 2.31 (s, 3H), 2.47-2.54 (m, 4H; overlap with solvent peak), 2.76-2.83 (m, 1H), 2.85- 3.05 (m, 3H), 3.08-3.23 (m, 2H), 3.30-3.47 (m, 3H; overlapping with solvent peaks), 5.29 (s, 2H), 6.92 (s, 1H), 7.18-7.25 (m, 2H), 7.54-7.63 (m, 1H), 7.80 (t, 1H), 8.48 (s, 1H).

Example 415 Racemic-N- [2-amino-2- (2-methyl-1,3-thiazol-4-yl) ethyl] -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide tricarboxylate

100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxylic acid from Example 21A, 137 mg (0.36 mmol) of HATU and 121 mg (1.20 mmol) of 4-methylmorpholine were first placed in 1.5 ml of DMF, and the mixture was stirred at RT for 60 min. Then 69 mg (0.30 mmol) of racemic-1- (2-methyl-1,3-thiazol-4-yl) ethane-1,2-diamine dihydrochloride was added and the mixture was stirred at RT to Overnight. The reaction mixture was purified by preparative HPLC (RP-C18, mobile phase: acetonitrile / water gradient with 0.05% formic acid). This gave 18 mg (10% of theory) of the title compound.

LC-MS (Method 2): R _t = 0.61min

MS (ESI +): m / z = 472 (M-3HCO ₂ H + H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.35 (s, 3H), 2.40 (s, 3H), 2.70 (s, 3H), 3.71-3.88 (m, 2H), 4.60- 4.68 (m, 1H), 5.32 (s, 2H), 7.13 (br.s, 1H), 7.21-7.28 (m, 2H), 7.56-7.65 (m, 1H), 7.65 (s, 1H), 8.06 ( br.s, 1H), 8.44-8.55 (2 br.s, 4H).

Example 416 Racemic-N- (2-amino-1-cyanoethyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2 -a] pyridine-3-carboxamide

151 mg (0.23 mmol) of racemic- {2-cyano-2-[({8-[(2,6-difluorobenzyl) oxy]]-2,6-dimethylimidazole) from Example 420A Benzo [1,2-a] pyridin-3-yl} carbonyl) amino] ethyl} carbamate benzyl trifluoroacetate and 50 mg of 10% activated carbon palladium (0.05 mmol) in 6 ml of ethanol The mixture was hydrogenated at room temperature and atmospheric pressure for 2 h. The reaction mixture was filtered through celite, the filter cake was washed with ethanol and the filtrate was concentrated. The residue was treated in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by thick layer chromatography (mobile phase: dichloromethane / methanol = 10/1). This gave 4 mg of the title compound (4% of theory).

LC-MS (Method 2): R _t = 0.62min

MS (ES +): m / z = 400 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 2.33 (s, 3H), 2.93-3.10 (m, 2H), 4.82-4.82 (t, 1H), 5.30 (s, 2H), 6.98 (s, 1H), 7.20-7.26 (m, 2H), 7.51-7.66 (m, 1H), 8.47 (s, 1H), [additional signal under solvent peak].

B. Evaluation of pharmacological activity

Use the following abbreviations: ATP adenosine triphosphate

Brij35 polyoxyethylene (23) lauryl ether

BSA bovine serum albumin

DTT Dithiothreitol

TEA Triethanolamine

The pharmacological effects of the compounds of the invention can be shown by the following analysis:

B-1. Measurement of sGC enzyme activity by detecting PPi

Soluble guanylate cyclase (sGC) is converted into cGMP and gum phosphate (PPi) by stimulating GTP. PPi is detected by means of the method described in WO 2008/061626. The signal generated during the test increased as the reaction progressed and was used as a measure of sGC enzyme activity. With the aid of the PPi reference curve, enzymes can be qualitatively known using known methods, such as related conversion rates, irritability, or Michaelis constant.

Test execution

The test was performed by using 29 μl of an enzyme solution (0-10 nM soluble guanylate cyclase (prepared according to Hönicka et al., Journal of Molecular Medicine 77 (1999) 14-23)) in 50 mM TEA, 2 mM magnesium chloride, 0.1% The solution in BSA (dissolved fraction V), 0.005% Brij 35, pH 7.5) was first introduced into a microplate, and 1 μl of a stimulator solution (0-10 μM 3-morpholinosddnimine) was added. , SIN-1, Merck dissolved in DMSO). The mixture was incubated at RT for 10 min. Add 20 μl of detection mixture (1.2nM firefly luciferase (Photinus pyralis Luziferase, Promega), 29 μM dehydrofluorescein (prepared according to Bitler & McElroy, Arch. Biochem. Biophys. 72 (1957) 358), 122 μM Luciferin (Promega), 153 μM ATP (Sigma) and 0.4 mM DTT (Sigma) were dissolved in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5). The enzyme reaction was started by adding 20 μl of a matrix solution (1.25 mM guanosine 5'-triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (dissociation fraction V), 0.005% Brij 35, pH 7.5) and The photometer continuously measures.

B-2. Effect on recombinant guanylate cyclase reporter cell line

The cellular effects of the compounds of the present invention were determined on guanylate cyclase-reported cell lines as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

The representative MEC values (MEC = minimum effective concentration) of the compounds of the present invention are shown in the following table (in some cases the average value obtained from individual determinations):

B-3. Vasodilator effect in vitro

The rabbit's neck was stunned and blood was drawn. Remove the aorta, remove the adherent tissue, divide into 1.5mm wide rings, and place them individually at 37 ° C in a 5-ml organ bath pre-loaded with carbogen-gassed Krebs-Henzlette solution , Which contains the following compositions (each mM): sodium chloride: 119; potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassium dihydrogen phosphate: 1.2; sodium bicarbonate : 25; glucose: 10. The contractile force was recorded in Statham UC2 cells, amplified and digitized via an A / D converter (DAS-1802 HC, Keithley Instruments Munich) and recorded in parallel on a tape recorder. Shrinkage occurs, and phenylephedrine is added to the bath at a cumulative increasing concentration. After several control cycles, in each subsequent run, the test substance was added in increasing doses, and the amount of shrinkage was compared with the amount of shrinkage achieved in the previous run. This term is used to calculate the concentration (IC ₅₀ value) required to reduce the amount by 50% of the control value. The standard application amount is 5 μl, and the proportion of DMSO in the bath solution is quite 0.1%.

B-4. Measurement of blood pressure in anesthetized rats

Male Wester rats weighing 300-350 g were anesthetized with thiopental (100 mg / kg i.p.). After gas dissection, a catheter for measuring blood pressure was placed into the femoral artery. The test substance solution was administered orally by tube feeding or intravenously via the femoral vein (Stasch et al. Br. J. Pharmacol. 2002; 135: 344-355).

B-5. Radiotelemetry blood pressure measurement in awake spontaneously hypertensive rats

A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA was used to measure blood pressure in awake rats as follows.

This system consists of three main components: a Physiotel® Telemetry Transmitter receiver (Physiotel® Receiver), which is connected to a data acquisition computer via a multiplexer (DSI Data Exchange Matrix) .

The telemetry system provides awake rats to continuously capture blood pressure, heart rate and body movements in their conventional living spaces.

Animal material

Adult female, spontaneously hypertensive rats (SHR Okamoto) weighing> 200 g were used for the study. From Okamoto Kyoto Medical College, the 1963 SHR / NCrl was mated with male Wester Kyoto rats with significantly increased blood pressure and females with slightly increased blood pressure and was shipped to the National Institutes of Health as F13.

After the launcher was implanted, the experimental animals were individually housed in type 3 Makrolon cages. It has free access to standard feed and water.

The day-night rhythm in the laboratory is changed by indoor lighting at 06:00 and 19:00.

Transmitter implant

The TA11 PA-C40 telemetry transmitter used was surgically implanted into experimental animals under sterile conditions at least 14 days before the first test. Animals equipped with this instrument can be used again after wound healing and implant integration.

Implantation was performed. The fasted animals were anesthetized with pentobarbital (Nembutal, Sanofi, 50 mg / kg intraperitoneally) and shaved and disinfected on the abdominal side over a large area. After opening the abdominal cavity along the white line, insert the fluid-filled system measurement catheter into the descending aorta above the bifurcation in the direction of the head and cover. Tissue adhesive (VetBonDTM, 3M) was used to fasten. The transmitter shell is fixed intraperitoneally to the abdominal wall muscles, and the wound is closed layer by layer.

After the surgery, antibiotics were given to prevent infection (Tardomyocel COMP Bayer 1ml / kg subcutaneously).

Substances and solutions

Unless otherwise stated, the test substances were administered orally to the animal group by gastric tube in each case (n = 6). The test substance is dissolved in a suitable solvent mixture or suspended in 0.5% strength Tylose, corresponding to an application amount of 5 ml / kg body weight.

A group of animals treated with a solvent was used as a control.

Test procedure

This telemetry device is installed on 24 animals. Each test is recorded with a test number (V test date).

The instrumented rats living in this unit were each equipped with their own receiving antenna (1010 Receiver, DSI).

The implanted transmitter can be activated externally via a built-in magnetic switch. Switch it to launch at the beginning of the test. The transmitted signal can be recorded online by the data acquisition system (DataquestTM A.R.T., DSI for Windows) and processed appropriately. Each time the data is stored in a folder open to the trial number.

In this standard procedure, the following are measured for 10 seconds each: systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

Mean arterial pressure (MAP)

Heart rate (HR)

Activity (ACT).

Recording of measured values is repeated at 5-minute intervals under computer control. The recorded source data as absolute values are corrected in the graph with the currently measured atmospheric pressure (ambient pressure Reference monitor; APR-1) and stored in separate data. Further technical details can be found in the extensive literature of the manufacturer (DSI).

Unless otherwise stated, test substances are administered at 09.00 on the day of the test. After application, the above parameters were measured for 24 hours.

Evaluation

After the experiment is finished, the individual data recorded are classified by the analysis software (DATAQUEST TM A.R.T.TM ANALYSIS). The blank value is 2 hours before the application, so the selected data set includes the period from 07:00 on the test day to 09:00 on the next day.

With the average value measurement, the data can be smoothed in advance (15-minute average) and the text file can be converted into a storage medium. Pre-classified and compressed measurements are transferred to an Excel template and presented in a table. The recorded data is stored in a special folder with the test number on the test day. The results and test methods are sorted by numbers in paper form and archived in folders.

literature

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured with Radio-Telemetry. Physiology & Behavior 55 (4): 783-787, 1994.

B-6. Determination of pharmacokinetic parameters after intravenous and oral administration

The pharmacokinetic parameters of the compounds of the present invention were measured in male CD-1 mice, male Wester rats, and female Miguel dogs. The intravenous administration of each mouse and rat was performed with a species-specific serous / DMSO formulation, while the dog in this case was formulated with water / PEG400 / ethanol Substance to administer. In all species, oral administration of the dissolved substance is based on a water / PEG400 / ethanol formulation, via tube feeding. The blood draw of the rats was simplified by inserting a silicone catheter into the right external jugular vein before the administration of the substance. This procedure was performed at least one day before the experiment with isoflurane analgesics and analgesics (atropin / Rimadyl (3/1) 0.1ml subcutaneous injection). After the substance is administered, blood is drawn within a time window that includes an endpoint time point of at least 24 to at most 72 hours (typically more than 10 time points). When blood is drawn, the blood line enters a heparinized test tube. The plasma was then obtained by centrifugation and stored at -20 ° C as needed until further processing.

An internal standard (which may also be a chemically unrelated substance) is added to the samples, calibration samples, and designations of the compounds of the invention, and the protein is then precipitated via excess acetone. A buffer solution meeting the LC conditions was added and then vortexed, followed by centrifugation at 1000 g. The supernatant was analyzed by LC-MS / MS using a C18 reverse phase column and a variable mobile phase mixture. Ion chromatograms extracted from selected ion monitoring experiments to quantify substances by peak height or area.

Plot the measured plasma concentration / time using an effective pharmacokinetic calculation program to calculate pharmacokinetic parameters such as AUC, _Cmax , t _1/2 (endpoint half-life), F (bioavailability), MRT (Mean residence time) and CL (clearance).

Because the substance is quantified in plasma, the blood / plasma distribution of the substance must be determined so that pharmacokinetic parameters can be adjusted accordingly. For this purpose, a defined amount of the substance is cultured in heparinized whole blood of the indicated species in a rock-rock mixture for 20 min. After centrifugation at 1000 g, the plasma concentration is measured and determined by calculating the ratio of C _blood / C _plasma (by LC-MS / MS; see above).

Table B shows data for representative compounds of the invention after intravenous administration in rats:

B-7. Metabolic research

In order to determine the metabolic properties of the compounds of the present invention, they were cultured with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes or primary fresh hepatocytes from various animal species (such as rats and dogs) and human origin to Obtain and compare information on metabolites that are substantially intact in stage I and II of the liver, and on enzymes involved in metabolism.

The compound of the present invention is cultured at a concentration of about 0.1-10 μM. In this regard, a stock solution of the compound of the present invention dissolved in acetonitrile having a concentration of 0.01 to 1 mM was prepared, and then pipetted into the culture mixture at a dilution of 1: 100. Liver microsomes and recombinant enzymes were composed of 1 mM NADP ⁺ , 10 mM glucose 6-phosphate, and 1 unit of glucose 6-phosphate dehydrogenase in 50 mM potassium phosphate buffer pH 7.4 at 37 ° C. Cultured under NADPH-production system. Primary hepatocytes were also cultured at 37 ° C in a suspension of Williams E medium. After a culture time of 0-4 h, the culture mixture was stopped with acetonitrile (final concentration about 30%), and the protein was centrifuged out at about 15 000 x g. The samples thus stopped were analyzed directly or stored at -20 ° C until analysis.

Analysis was performed by high performance liquid chromatography with ultraviolet and mass detection (HPLC-UV-MS / MS). In this regard, the supernatant of the culture sample was chromatographed on a suitable C18 reverse phase column and a variable mobile phase mixture of acetonitrile and 10 mM ammonium formate aqueous solution or 0.05% ammonium formate. UV chromatograms are combined with mass spectrometry data for metabolite identification, structural analysis, and quantitative estimation, as well as for quantitative metabolic evaluation of compounds of the invention in culture mixtures.

B-8. Caco-2 permeability test

The permeability of the test substance was determined using the Caco-2 cell line, an established predictive model of the permeability of the gastrointestinal barrier in vitro (Artursson, P. and Karlsson, J. (1991). Oral drug absorption in humans and human intestines Correlation between apparent drug permeability coefficients of epidermal (Caco-2) cells (Biochem. Biophys. 175 (3), 880-885). CaCo-2 cells (ACC No. 169, DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany) were inserted into a 24-well plate and cultured for 14 to 16 days. For permeability studies, the test substance was dissolved in DMSO and diluted with transport buffer (Hanck's buffered saline solution, Gibco / Invitrogen, containing 19.9 mM glucose and 9.8 mM HEPES) to the final test concentration. To determine the permeability of the test substance from the top to the base (P _app AB), the solution including the test substance was placed on the basal side of the Caco-2 cell monolayer, and the transport buffer was placed on the top test. At the beginning of the experiment, samples were taken from individual donor chambers to ensure mass balance. After two hours of incubation at 37 ° C, samples were taken from the second chamber. The samples were analyzed by LC-MS / MS and the apparent permeability coefficient (P _app ) was calculated. For each cell monolayer, the permeability of Fluorescent Yellow was measured to determine cell layer integrity. In each test, the permeability of atenolol (a marker of low permeability) and sulfasalazine (a marker of active excretion) were also determined as qualitative controls.

B-9.hERG potassium current analysis

The hERG (human ether-a-go-go related gene) potassium current essentially causes repolarization of the human heart action potential (Scheel et al., 2011). By suppressing this current through medicine, in rare cases it can cause potentially fatal arrhythmias and therefore research in the early stages of drug development.

The functional hERG analysis used herein is based on a recombinant HEK293 cell line (Zhou et al., 1998) that stably expresses the KCNH2 (HERG) gene. These cells were examined using an automated system (Patchliner ^™ ; Nanion, Munich, Germany) for controlling membrane voltage and measuring hERG potassium current at room temperature using whole cell voltage clamping technology (Hamill et al., 1981). PatchControlHT ^TM software (Nanion) controls the Patchliner system; data collection and data analysis. The voltage was controlled by 2 EPC-10 quadruple amplifiers controlled by PatchMasterPro ^™ software (both HEKA Elektronik, Lambrecht, Germany). The NPC-16 chip (~ 2MΩ; Nanion) with median resistance was used as the planar substrate for the voltage clamping experiment.

NPC-16 wafers were filled with intracellular and extracellular solutions (see Himmel, 2007) and cell suspensions. After the formation of the GigaOhm seal and the establishment of the whole-cell mode (including most automated qualitative control steps), repair the cell membrane to a maintenance potential of -80mV. The subsequent voltage clamping method changes the control voltage to + 20mV (for 1000ms), -120mV (for 500ms), and returns to the maintenance potential of -80mV; repeat every 12 seconds. After the initial stabilization phase (approximately 5-minutes), the test substance (for example, 0.1, 1 and 10 μmol / l) is pipetted in at increasing concentrations (each concentration exhibits approximately 5-6 minutes), followed by several cleaning steps .

The amplitude of the incoming wake generated by changing the potential from + 20mV to -120mV is used to quantify the hERG potassium current and is expressed as a function of time (IgorPro ^TM software). The amplitude of the current at the end of different intervals (such as the stabilization phase before the test substance, the first / second / third concentration of the test substance) is used to establish the concentration / activity curve, which is used to calculate the half maximum inhibition of the test substance concentration IC _50.

Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pfluegers Arch 1981; 391: 85-100.

Himmel HM. Suitability of commonly used excipients for electrophysiological in-vitro safety pharmacology assessment of effects on hERG potassium current and on rabbit Purkinje fiber action potential. J Pharmacol Toxicol methods 2007; 56: 145-158.

Scheel O, Himmel H, Rascher-Eggstein G, Knott T. Introduction of a modular automated voltage-clamp platform and its correlation with manual human ether-a-go-go related gene voltage-clamp data. Assay Drug Dev Technol 2011; 9 : 600-607.

Zhou ZF, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, January CT. Properties of hERG channels stably expressed in HEK293 cells studied at physiological temperature. Biophys J 1998; 74: 230-241.

C. Exemplary Examples of Pharmaceutical Compositions

The compounds of the invention can be converted into pharmaceutical preparations in the following ways:

Lozenges: composition:

100 mg of a compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate .

The weight of the lozenge is 212mg, the diameter is 8mm, and the radius of curvature is 12mm.

Manufacturing:

The compound of the present invention, lactose and starch are granulated in an aqueous solution of PVP at a concentration of 5% (m / m). The granules were dried and then mixed with magnesium stearate for 5 minutes. The mixture is compressed with a conventional tablet press (see above for the tablet type). The guiding pressure for pressing is 15kN.

Suspensions for oral administration: composition:

The compounds of the present invention 1000mg, 1000mg in ethanol (96%), Rhodigel ^® (xanthan gum from FMC Corporation, Pennsylvania, USA) 400mg and 99g of water.

A 10 ml oral suspension corresponds to a single dose of 100 mg of a compound of the invention.

Manufacturing:

Rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Add water while stirring. The mixture was stirred for about 6 hours until Rhodigel was fully expanded.

Solutions for oral administration: composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of an oral solution is equivalent to a single dose of 100 mg of the compound of the invention.

Manufacturing:

The compound of the present invention is suspended in a mixture of polyethylene glycol and polysorbate with stirring. The stirring procedure is continued until the compound of the invention is completely dissolved.

Intravenous solution:

The compounds of the present invention are dissolved in physiologically tolerant solvents (eg, isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution) with less than saturated solubility. The resulting solution was sterilized by filtration and used to fill sterile and pyrogen-free containers.

Claims (19)

A compound selected from the group consisting of: Enantio - N -[(2S) -amino-2-methylbutyl] -8-[(2,6-difluorobenzyl) oxy]- 2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

Enantiomer - N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2- a) Pyridine-3-carboxamide (mirror isomer B)

Enantiomer -N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl ) Oxy] imidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

Enantiomer -N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

Enantiomer -N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-di Methylimidazo [1,2-a] pyridine-3-carboxamide (Mirror image isomer A)

Enantiomer -N- (2-amino-3-fluoro-2-methylpropyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

Enantio -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer B)

Enantio -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [ 1,2-a] pyridine-3-carboxamide (mirror isomer A)

Racemic -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamidate

Enantiomer -N- (2-amino-3-fluoro-2-methylpropyl) -2,6-dimethyl-8-[(2,3,6-trifluorobenzyl) oxy] imidazole Benzo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

Enantiomer -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2 -Methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

Enantiomer -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -6- (difluoromethyl) -2 -Methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

Enantiomer -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) oxy] -6- (fluoromethyl) -2- Methylimidazo [1,2-a] pyridine-3-carboxamide

For example, the compound in the scope of application for the first item, wherein the compound is enantio - N -[(2S) -amino-2-methylbutyl] -8-[(2,6-difluorobenzyl) oxy ] -2,6-Dimethylimidazo [1,2-a] pyridine-3-carboxamide (Mirror image isomer A)

For example, the compound of the scope of application for patent No. 1 wherein the compound is enantio - N- (2-amino-2-methylbutyl) -8-[(2,6-difluorobenzyl) oxy]- 2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

For example, the compound in the scope of application for patent No. 1 wherein the compound is enantio -N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -2,6-dimethyl- 8-[(2,3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer B)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -8-[(2,6- Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-5,5,5-trifluoro-2-methylpentyl) -8-[(2,6- Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer A)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-3-fluoro-2-methylpropyl) -2,6-dimethyl-8-[(2 , 3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) Oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer B)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) Oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer A)

For example, the compound in the scope of application for patent No. 1 wherein the compound is racemic -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl ) Oxy] -2,6-dimethylimidazo [1,2-a] pyridine-3-carboxamidate

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-3-fluoro-2-methylpropyl) -2,6-dimethyl-8-[(2 , 3,6-trifluorobenzyl) oxy] imidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer A)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) Oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxamide (mirror isomer B)

For example, the compound in the scope of application for the first item, wherein the compound is enantio -N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) Oxy] -6- (difluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxamidine (mirror isomer A)

For example, the compound in the scope of application for the first item, wherein the compound is enantio-N- (2-amino-3-fluoro-2-methylpropyl) -8-[(2,6-difluorobenzyl) Oxy] -6- (fluoromethyl) -2-methylimidazo [1,2-a] pyridine-3-carboxamide

Method for preparing compound of formula (I)

Where A represents CH ₂ , R ¹ represents phenyl, wherein phenyl is substituted with 2 to 3 fluorines, R ² represents methyl, and R ³ represents a group of the formula

Where * represents the carbonyl attachment point, L ^1A represents a bond, L ^1B represents a bond, L ^1C represents a bond, R ⁷ represents hydrogen, R ⁸ represents hydrogen, and R ⁹ represents (C ₁ -C ₄ ) -alkyl, where (C ₁ -C ₄ ) -alkyl is substituted up to five times with fluorine, R ¹⁰ represents methyl or ethyl, R ¹¹ represents hydrogen, R ¹² represents hydrogen, R ⁴ represents hydrogen, R ⁵ represents hydrogen or methyl, and R ⁶ represents Hydrogen, characterized in that [A] converts a compound of formula (II)

Wherein A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the definitions shown above, and T ¹ represents (C ₁ -C ₄ ) -alkyl or benzyl, at 0 ° C to +50 A temperature range of ℃, at a pressure of 0.5 to 5 bar, in an inert solvent selected from the group consisting of alcohols, ethers, acetone, dichloromethane, dimethylformamide, dimethylmethane and mixtures thereof There may also be water, a base selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates and alkaline earth metal carbonates, or selected from the group consisting of sulfuric acid, hydrogen chloride / hydrochloric acid, and bromination Hydrogen / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and a group of mixtures thereof can be added to react in the presence of an acid to obtain the formula ( III) Carboxylic acid

Wherein A, R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ each have the definitions shown above, and are subsequently selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons and others selected from acetone and ethyl acetate. , Acetonitrile, pyridine, dimethylmethane, N, N-dimethylformamide, N, N-dimethylacetamide, N, N'-dimethylpropylene urea (DMPU) or N-formamidine In an inert solvent of the group consisting of a solvent of a pyrrolidone (NMP) or a mixture thereof, under the amidine coupling conditions and selected from the group consisting of O- (benzotriazol-1-yl) -N, N, N ', N' -Tetramethyltetrafluoroborate

(TBTU) in combination with N-methylmorpholine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylhexafluorophosphate

(HATU) Condensing agent in the group consisting of N, N-diisopropylethylamine and 1-chloro-N, N, 2-trimethylprop-1-ene-1amine at 0 ° C Reacts with amines of formula (IV-A) at a temperature range of + 60 ° C, at a pressure of 0.5 to 5 bar,

Wherein L ^1A , L ^1B , L ^1C , L ² , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each have the definitions shown above, and R ^11A and R ^12A have the above definitions of R ¹¹ and R ¹² respectively, or Represents an amine protecting group. For example, the method of claim 15 in the patent application range, wherein the amine protecting group is selected from the group consisting of a third butoxycarbonyl group, a benzyloxycarbonyl group and a benzyl group. Method for preparing compound of formula (I)

Wherein the substituent is as defined in item 15 of the scope of patent application, which is characterized in that [B] the compound of formula (III-B)

R ² , R ⁴ , R ^5, and R ⁶ each have the definitions shown above, and are selected from the group consisting of ethers, hydrocarbons, halogenated hydrocarbons, and others selected from acetone, ethyl acetate, acetonitrile, pyridine, and dimethylene. Solvents of hydrazone, N, N-dimethylformamide, N, N-dimethylacetamide, N, N'-dimethylpropylene urea (DMPU) or N-methylpyrrolidone (NMP) In a group of inert solvents, the mixture is selected from the group consisting of TBTU and N-methylmorpholine, HATU and N, N-diisopropylethylamine, and 1-chloro-N under the amidine coupling condition. , N, 2-trimethylprop-1-ene-1amine combination under the condensing agent group, in the temperature range of 0 ℃ to +60 ℃, at a pressure of 0.5 to 5 bar, and formula (IV) Amine reaction to obtain a compound of formula (IA)

Wherein R ² , R ⁴ , R ⁵ , R ⁶ , L ^1A , L ^1B , L ^1C , L ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11A and R ^12A have the definitions shown above, then The benzyl group is removed from this compound by hydrogenolysis in an inert solvent in the presence of a palladium catalyst, and the resulting compound of formula (VA)

Wherein R ² , R ⁴ , R ⁵ , R ⁶ , L ^1A , L ^1B , L ^1C , L ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^11A and R ^12A each have the definitions shown above, React with a compound of formula (VI) in the presence of a base in an inert solvent

Wherein A and R ¹ each have the definition shown above, and X ¹ represents a leaving group, which is selected from the group consisting of chlorine, bromine, iodine, methanesulfonic acid group, trifluoromethanesulfonic acid group, or toluenesulfonic acid group. Group, followed by removal of any protecting groups present, and converting the resulting compound of formula (I) to its salt with (i) an acid or base as needed. A compound as claimed in any one of claims 1 to 14 for use in the manufacture of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal failure, thromboembolic disorders and arteries Hardened medicine. A pharmaceutical product comprising a compound according to any one of claims 1 to 14 of the scope of patent application and an inert, non-toxic, pharmaceutically suitable adjuvant combination.